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This report is written by MaltSci based on the latest literature and research findings

How does cell death signaling regulate tissue homeostasis? ​

Abstract ​

Cell death signaling is a fundamental biological process that plays a critical role in maintaining tissue homeostasis through various mechanisms, including apoptosis, necrosis, and autophagy. This review provides an overview of how these mechanisms contribute to cellular turnover, tissue repair, and immune regulation. Apoptosis, a highly regulated form of programmed cell death, ensures the removal of damaged or unnecessary cells, thus preventing the accumulation of dysfunctional cells that could disrupt tissue integrity. Recent studies have highlighted the importance of apoptotic signaling in communicating with neighboring cells, promoting their proliferation and differentiation to sustain tissue homeostasis. Necroptosis, another form of regulated cell death, has emerged as a significant player in immune responses and tissue homeostasis, particularly in the context of inflammation and pathogen defense. The interplay between these cell death modalities reveals a complex network that governs cellular fate in response to various stressors. Dysregulation of cell death signaling pathways can lead to pathological conditions such as cancer, neurodegenerative diseases, and autoimmune disorders, where the balance between cell survival and death is disrupted. Furthermore, the therapeutic implications of targeting cell death pathways are explored, including strategies for modulating apoptosis in cancer therapy, manipulating necroptosis to manage inflammation, and harnessing cell death mechanisms in regenerative medicine. Understanding the intricate relationship between cell death signaling and tissue homeostasis is essential for advancing therapeutic strategies in the biomedical field.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Overview of Cell Death Mechanisms
    • 2.1 Apoptosis: The Programmed Cell Death
    • 2.2 Necrosis and Necroptosis: Uncontrolled Cell Death
    • 2.3 Autophagy: A Dual Role in Cell Survival and Death
  • 3 Cell Death Signaling Pathways
    • 3.1 Extrinsic Pathway: Death Receptors and Their Ligands
    • 3.2 Intrinsic Pathway: Mitochondrial Regulation of Apoptosis
    • 3.3 Crosstalk Between Pathways: Integrating Cell Death Signals
  • 4 Role of Cell Death in Tissue Homeostasis
    • 4.1 Cellular Turnover and Tissue Renewal
    • 4.2 Tissue Repair Mechanisms Following Injury
    • 4.3 Immune System Regulation and Inflammation
  • 5 Dysregulation of Cell Death and Disease
    • 5.1 Cancer: Evasion of Apoptosis
    • 5.2 Neurodegenerative Diseases: Excessive Cell Death
    • 5.3 Autoimmune Disorders: Inflammation and Tissue Damage
  • 6 Therapeutic Implications
    • 6.1 Targeting Apoptotic Pathways in Cancer Therapy
    • 6.2 Modulating Necroptosis and Inflammation
    • 6.3 Regenerative Medicine: Harnessing Cell Death Mechanisms
  • 7 Conclusion

1 Introduction ​

Cell death signaling is an essential biological process that plays a pivotal role in maintaining tissue homeostasis. It encompasses various mechanisms, including apoptosis, necrosis, and autophagy, each contributing uniquely to cellular turnover, tissue repair, and the prevention of disease. The regulation of cell death is crucial not only for normal development and tissue maintenance but also for the immune response and the management of cellular stress. Dysregulation of these processes can lead to a myriad of pathological conditions, including cancer, neurodegenerative diseases, and autoimmune disorders. Therefore, understanding the intricate relationship between cell death signaling pathways and tissue homeostasis is paramount for advancing therapeutic strategies in regenerative medicine and oncology.

Historically, cell death was perceived primarily as a means to eliminate unwanted or damaged cells, often viewed as a passive endpoint of cellular life. However, contemporary research has illuminated the complex and dynamic nature of cell death, revealing its role as an active regulator of tissue architecture and function. Recent findings suggest that dying cells can emit signals that not only inform neighboring cells of their demise but also influence their behavior, promoting cellular proliferation and differentiation necessary for tissue regeneration and homeostasis [1][2]. This phenomenon, often referred to as "immunogenic cell death," highlights the dual role of cell death in both promoting tissue repair and, under certain conditions, contributing to tissue damage [3].

The current landscape of research on cell death signaling pathways has identified several key mechanisms, particularly the extrinsic and intrinsic apoptotic pathways, necroptosis, and the regulatory roles of inflammation [4][5]. The extrinsic pathway, mediated by death receptors such as Fas and TNF receptors, is critical for initiating apoptosis in response to extracellular signals. In contrast, the intrinsic pathway, which involves mitochondrial signaling, plays a crucial role in responding to internal cellular stressors [6]. Furthermore, necroptosis has emerged as a significant form of regulated cell death that contributes to tissue homeostasis and immune responses, particularly in the context of pathogen infection and inflammation [3].

In this review, we will systematically explore the multifaceted roles of cell death signaling in regulating tissue homeostasis. We will begin with an overview of the various mechanisms of cell death, including apoptosis, necrosis, and autophagy, emphasizing their distinct and overlapping roles in cellular fate determination. Following this, we will delve into the key signaling pathways involved in cell death, examining how these pathways interact and integrate to modulate cellular responses to stress and injury.

Subsequently, we will discuss the critical role of cell death in maintaining tissue homeostasis, focusing on processes such as cellular turnover, tissue repair mechanisms following injury, and the regulation of the immune system and inflammation. Understanding these processes is essential for elucidating how disruptions in cell death signaling can lead to disease. In particular, we will highlight the implications of dysregulated cell death in cancer, neurodegenerative diseases, and autoimmune disorders, where the balance between cell survival and death is often tipped, leading to pathological outcomes.

Finally, we will address the therapeutic implications of targeting cell death pathways in various diseases. We will explore potential strategies for modulating apoptotic pathways in cancer therapy, manipulating necroptosis and inflammation for therapeutic benefit, and harnessing the mechanisms of cell death in regenerative medicine to promote tissue repair and regeneration.

Through this comprehensive review, we aim to provide a deeper understanding of how cell death signaling intricately regulates tissue homeostasis and its implications for health and disease, thereby paving the way for future research in this critical area of biomedical science.

2 Overview of Cell Death Mechanisms ​

2.1 Apoptosis: The Programmed Cell Death ​

Cell death signaling plays a critical role in maintaining tissue homeostasis through various mechanisms, primarily by regulating apoptosis, a form of programmed cell death. Apoptosis is a tightly controlled process that eliminates damaged or unnecessary cells, thus preventing the accumulation of dysfunctional cells that could disrupt tissue function. The balance between cell proliferation and cell death is essential for tissue integrity and regeneration.

Recent findings indicate that apoptosis is not merely a means to dispose of cells but also serves as a regulatory mechanism that communicates with neighboring cells to influence their behavior. For instance, apoptotic bodies produced by dying cells can deliver instructive signals to adjacent healthy cells, prompting them to proliferate and maintain tissue homeostasis. This phenomenon is exemplified in epithelial tissues, where dying stem cells release Wnt8a-containing apoptotic bodies that activate Wnt signaling in neighboring basal stem cells, stimulating their division and sustaining the overall stem cell population in the tissue [2].

Moreover, cell death signaling can initiate a cascade of responses that affect not only local cell populations but also the broader tissue environment. Dying cells release a variety of signals, including low-molecular-weight molecules and proteins, which can influence the behavior of surrounding cells, promote tissue repair, and facilitate regeneration. For instance, in the context of hair follicle regeneration, the regression phase involves the elimination of epithelial cells through apoptosis, which is regulated by transforming growth factor (TGF)-β signaling. This process not only clears damaged cells but also modulates the stem cell pool, ensuring that tissue homeostasis is preserved [7].

The role of apoptosis in tissue homeostasis is further underscored by its interaction with other forms of cell death, such as necroptosis and pyroptosis, which can also impact tissue integrity and inflammatory responses. Necroptosis, for example, has been identified as an important component of immunogenic cell death (ICD), contributing to host defense mechanisms while also potentially causing tissue damage [3]. The intricate balance between different forms of cell death and their signaling pathways highlights the complexity of tissue homeostasis regulation.

In addition to the signaling pathways activated by apoptotic cells, the mechanisms governing cell death involve intricate interactions between organelles, particularly the endoplasmic reticulum (ER) and mitochondria. Mitochondria-associated membranes (MAMs) facilitate communication between these organelles, influencing the decision of a cell to undergo apoptosis or survive in response to stress [8]. The disruption of this balance can lead to pathological conditions, emphasizing the importance of precise regulation of cell death mechanisms in maintaining tissue health.

Overall, the signaling pathways involved in apoptosis and other forms of cell death are vital for regulating tissue homeostasis. They ensure the removal of damaged cells, promote the proliferation of healthy cells, and maintain the balance necessary for tissue integrity and regeneration. Disturbances in these processes can lead to various diseases, highlighting the significance of understanding cell death mechanisms in biomedical research and therapeutic development [9].

2.2 Necrosis and Necroptosis: Uncontrolled Cell Death ​

Cell death signaling plays a crucial role in regulating tissue homeostasis through various mechanisms that ensure a balance between cell proliferation, differentiation, and elimination. Among the different forms of cell death, necrosis and necroptosis are significant due to their distinct characteristics and implications for tissue integrity and immune responses.

Necrosis is often considered an uncontrolled form of cell death that typically results from acute cellular injury, leading to the release of intracellular contents into the extracellular space. This process can trigger inflammatory responses and tissue damage, which may disrupt homeostasis. The uncontrolled nature of necrosis can contribute to a variety of pathological conditions, including acute inflammation and chronic diseases, as it can exacerbate tissue injury and hinder the regenerative capacity of the affected area.

On the other hand, necroptosis is a regulated form of necrosis that is mediated by specific signaling pathways. It is recognized as a type of immunogenic cell death (ICD), which means it can elicit an immune response. Recent studies indicate that necroptosis is a critical component of host defense mechanisms against pathogen infections, contributing to inflammation and the immune response while also participating in tissue homeostasis and cancer response to immunotherapy. This dual role highlights the complexity of necroptosis as it can promote both protective and damaging effects depending on the context of its activation [3].

The signaling pathways that govern necroptosis involve several key molecules, including receptor-interacting protein kinases (RIPK1 and RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL). When cells undergo necroptosis, these proteins orchestrate a series of events that lead to cellular swelling, membrane rupture, and the release of damage-associated molecular patterns (DAMPs), which further amplify inflammatory signals. This response can attract immune cells to the site of tissue damage, promoting repair and regeneration. However, if dysregulated, necroptosis can lead to excessive inflammation and contribute to chronic inflammatory diseases [3].

Furthermore, the communication between dying cells and their neighboring healthy cells is vital for maintaining tissue homeostasis. Dying cells can release signals that influence the behavior of adjacent cells, promoting proliferation and differentiation. For instance, apoptotic bodies released from dying cells can carry Wnt signaling molecules that stimulate the proliferation of surrounding stem cells, thereby facilitating tissue maintenance and repair [2]. This indicates that while necrosis and necroptosis may initially appear detrimental, they can also activate regenerative processes when appropriately regulated.

In summary, cell death signaling, particularly through mechanisms like necroptosis, plays a pivotal role in regulating tissue homeostasis by balancing cell elimination with regeneration. The interplay between cell death and immune responses is complex, as it can lead to both protective outcomes and potential tissue damage, underscoring the need for precise regulation of these processes to maintain tissue integrity and function [3][9].

2.3 Autophagy: A Dual Role in Cell Survival and Death ​

Cell death signaling plays a crucial role in regulating tissue homeostasis by maintaining a balance between cell proliferation, differentiation, and elimination. Various forms of cell death, including apoptosis, necroptosis, and autophagy, contribute to this regulatory network, influencing the overall health and functionality of tissues.

Apoptosis, often regarded as a programmed form of cell death, is essential for eliminating damaged or unwanted cells without provoking inflammation. It is a highly regulated process that involves a cascade of signaling pathways, with the CD95 (APO-1/Fas) system being one of the central regulatory mechanisms. Disruptions in apoptosis can lead to various diseases, including lymphoproliferative disorders and autoimmune conditions, highlighting its importance in maintaining tissue homeostasis [10].

Necroptosis, another form of programmed cell death, has been identified as a significant player in tissue homeostasis and immune responses. Recent studies indicate that necroptosis can trigger inflammation and is involved in host defense against infections, as well as responses to cancer immunotherapy. This form of cell death is characterized by the release of damage-associated molecular patterns (DAMPs), which can stimulate an immune response, thereby contributing to tissue repair and regeneration [3].

Autophagy, a cellular process that degrades and recycles cellular components, also has a dual role in cell survival and death. Under stress conditions, autophagy can promote cell survival by removing damaged organelles and proteins, thereby preventing apoptosis. However, excessive autophagy can lead to cell death, especially in the context of nutrient deprivation or severe cellular stress. This duality makes autophagy a critical factor in regulating cellular fate and, consequently, tissue homeostasis [9].

The interaction between these cell death modalities is complex and context-dependent. For instance, dying cells can influence neighboring cells through the release of signals that promote proliferation and differentiation, thereby aiding in tissue maintenance. In epithelial tissues, for example, dying cells can release apoptotic bodies that contain Wnt signaling molecules, which stimulate adjacent stem cells to proliferate and maintain the epithelial barrier [2].

Moreover, the crosstalk between organelles, particularly the endoplasmic reticulum (ER) and mitochondria, is pivotal in determining the fate of the cell. Mitochondria-associated membranes (MAMs) facilitate the communication between these organelles, influencing both autophagy and apoptosis. Disruptions in this signaling can lead to cell death or survival, further emphasizing the role of organelle interactions in regulating tissue homeostasis [8].

In summary, cell death signaling mechanisms, including apoptosis, necroptosis, and autophagy, are integral to maintaining tissue homeostasis. They not only regulate the elimination of damaged or unnecessary cells but also facilitate communication and signaling among neighboring cells to promote tissue repair and regeneration. Understanding these processes and their interplay is crucial for developing therapeutic strategies in regenerative medicine and treating various diseases associated with dysregulated cell death.

3 Cell Death Signaling Pathways ​

3.1 Extrinsic Pathway: Death Receptors and Their Ligands ​

Cell death signaling plays a crucial role in regulating tissue homeostasis, particularly through the extrinsic pathway involving death receptors and their ligands. This pathway is primarily characterized by the activation of specific death receptors on the cell surface, which, upon binding with their corresponding ligands, initiate a cascade of signaling events leading to apoptosis. The extrinsic pathway is mediated by various ligands such as tumor necrosis factor-alpha (TNF-α), Fas ligand, and TRAIL (TNF-related apoptosis-inducing ligand), which interact with their respective receptors including TNF receptor 1, Fas, and others.

The activation of these death receptors triggers the recruitment of adaptor proteins, leading to the formation of the death-inducing signaling complex (DISC). This complex subsequently activates initiator caspases, particularly caspase-8, which in turn activates effector caspases, such as caspase-3, culminating in the execution of apoptosis. This process is essential for the elimination of damaged or unwanted cells, thereby maintaining cellular integrity and preventing the development of pathological conditions such as cancer and autoimmune diseases (Seo et al., 2019; Jin & El-Deiry, 2005).

In addition to apoptosis, the extrinsic pathway can also lead to necroptosis, a form of programmed cell death that occurs when caspase-8 activity is inhibited. Necroptosis is characterized by a pro-inflammatory response, which can be beneficial in certain contexts, such as during pathogen infection, but may also contribute to tissue damage if not properly regulated (Roberts et al., 2022; Yin et al., 2024).

The balance between apoptosis and necroptosis is critical for maintaining tissue homeostasis. Dysregulation of these pathways can lead to excessive cell death or survival, resulting in various diseases. For instance, insufficient apoptosis can contribute to tumorigenesis, while excessive necroptosis can lead to chronic inflammation and tissue damage (Wang et al., 2024). Moreover, the interplay between different cell death modalities, such as autophagy and apoptosis, further complicates the regulation of tissue homeostasis, as these processes can influence each other through shared signaling pathways and molecular effectors (Gupta et al., 2021).

Furthermore, the clearance of apoptotic cells through efferocytosis, the process by which phagocytic cells engulf dying cells, is essential for preventing the release of potentially harmful cellular contents and maintaining tissue homeostasis. This process is mediated by specific signals, such as externalized phosphatidylserine on apoptotic cells, which are recognized by phagocytes, thus facilitating the removal of dead cells without eliciting an inflammatory response (Kumar et al., 2017).

In summary, cell death signaling pathways, particularly the extrinsic pathway involving death receptors and their ligands, are integral to the regulation of tissue homeostasis. They ensure the proper elimination of damaged or unnecessary cells, maintain the balance between different forms of cell death, and promote the clearance of dead cells, thereby preventing inflammation and supporting tissue repair and regeneration. Understanding these mechanisms provides valuable insights into potential therapeutic strategies for diseases characterized by dysregulated cell death (Kist & Vucic, 2021; Kopeina et al., 2025).

3.2 Intrinsic Pathway: Mitochondrial Regulation of Apoptosis ​

Cell death signaling plays a crucial role in regulating tissue homeostasis through the mechanisms of apoptosis, which is a highly controlled form of programmed cell death. Apoptosis is vital for maintaining cellular balance within tissues, facilitating processes such as embryonic development, tissue remodeling, and the elimination of damaged or unnecessary cells. The regulation of apoptosis is primarily mediated through two main pathways: the extrinsic (death receptor) pathway and the intrinsic (mitochondrial) pathway, both of which converge on the activation of caspases, the key executors of the apoptotic program.

The intrinsic pathway, particularly, is tightly linked to mitochondrial function and integrity. This pathway is initiated by various stress signals that activate pro-apoptotic members of the Bcl-2 family of proteins, leading to mitochondrial outer membrane permeabilization (MOMP). This process results in the release of apoptogenic factors, such as cytochrome c, from the mitochondria into the cytosol, which subsequently activates caspases and triggers the apoptotic cascade (Pandarpurkar et al. 2003; Khosravi-Far & Degli Esposti 2004).

Mitochondria are not only involved in the execution of apoptosis but also play a pivotal role in maintaining cellular health and homeostasis. They serve as the central regulators of energy metabolism and cellular signaling. Any dysfunction in mitochondrial activity can lead to the deregulation of apoptosis, contributing to various pathologies, including cancer, autoimmune diseases, and neurodegenerative disorders (Galluzzi et al. 2012; Poltorak 2022).

The delicate balance between pro-apoptotic and anti-apoptotic signals is essential for tissue homeostasis. In healthy tissues, this balance ensures that damaged or potentially harmful cells undergo apoptosis, thereby preventing the accumulation of dysfunctional cells that could lead to disease. Conversely, in conditions where apoptosis is inhibited, such as in many cancers, there is a survival advantage for neoplastic cells, allowing them to proliferate uncontrollably (Debatin & Krammer 2004; Roberts et al. 2022).

Moreover, the regulation of apoptosis through mitochondrial pathways is intricately linked to other cellular processes, such as autophagy and necroptosis, which also contribute to tissue homeostasis and response to stress (Zhang et al. 2025). The interplay between these pathways underscores the complexity of cell death signaling in maintaining the balance between cell survival and death, ultimately influencing tissue integrity and function.

In summary, the regulation of apoptosis via intrinsic signaling pathways, particularly through mitochondrial mechanisms, is fundamental to maintaining tissue homeostasis. By ensuring the removal of damaged or unnecessary cells while preserving healthy ones, these pathways contribute to overall tissue health and the prevention of disease.

3.3 Crosstalk Between Pathways: Integrating Cell Death Signals ​

Cell death signaling plays a crucial role in regulating tissue homeostasis through various mechanisms that ensure a balance between cell survival and death. This balance is essential for normal development, tissue maintenance, and the prevention of diseases such as cancer, autoimmune disorders, and neurodegenerative conditions.

Apoptosis, a form of programmed cell death, is a key player in maintaining tissue homeostasis. It is tightly regulated by complex signaling pathways that include both extrinsic and intrinsic mechanisms. The extrinsic pathway is activated by death receptors on the cell surface, such as tumor necrosis factor receptor 1 (TNFR1) and Fas, which trigger a cascade of events leading to the activation of caspases, the effector enzymes of apoptosis. The intrinsic pathway, on the other hand, is regulated by mitochondrial signals and involves the release of pro-apoptotic factors from mitochondria, leading to the formation of the apoptosome and subsequent caspase activation [11].

In addition to apoptosis, other forms of regulated cell death, such as necroptosis, pyroptosis, and autophagy-dependent cell death, contribute to tissue homeostasis. Necroptosis is a programmed form of necrosis that can occur when apoptosis is inhibited, often leading to inflammation [12]. Pyroptosis, which is associated with inflammation and the immune response, involves the activation of inflammatory caspases and results in cell lysis and the release of pro-inflammatory cytokines [3]. These different pathways can interact and influence each other, creating a complex network of signals that dictate cell fate in response to various physiological and pathological conditions [13].

Crosstalk between these pathways is vital for integrating cell death signals and responding appropriately to cellular stressors. For instance, the interplay between apoptosis and autophagy can determine cell fate under stress conditions. While autophagy typically promotes cell survival by degrading damaged organelles and proteins, excessive or dysregulated autophagy can lead to cell death [14]. Moreover, signals from dying cells can influence neighboring cells, promoting survival or death depending on the context, thereby affecting overall tissue health [15].

Ubiquitination, a post-translational modification, is also critical in regulating cell death pathways. It can modulate the stability and activity of key signaling proteins involved in apoptosis and necroptosis, thus influencing the balance between cell survival and death [16]. The understanding of these regulatory mechanisms has significant implications for therapeutic strategies aimed at restoring tissue homeostasis in various diseases [17].

In summary, cell death signaling pathways are intricately linked to tissue homeostasis through a balance of survival and death signals. The crosstalk between different forms of cell death, along with regulatory mechanisms such as ubiquitination, underscores the complexity of these processes and their importance in maintaining cellular and tissue integrity. Understanding these pathways provides insights into potential therapeutic interventions for diseases characterized by dysregulated cell death.

4 Role of Cell Death in Tissue Homeostasis ​

4.1 Cellular Turnover and Tissue Renewal ​

Cell death plays a critical role in regulating tissue homeostasis through various mechanisms that ensure the balance between cell loss and proliferation. Epithelial tissues, for example, require continuous removal and replacement of damaged cells to maintain a functional barrier. Research indicates that dying cells can influence the behavior of adjacent healthy cells, particularly stem cells, by providing instructive signals that drive cellular turnover. A study demonstrated that dying stem cells release Wnt8a-containing apoptotic bodies, which are engulfed by neighboring basal stem cells. This interaction activates Wnt signaling pathways, stimulating these stem cells to proliferate and thus maintain tissue-wide cell numbers. Inhibition of either the apoptotic process or Wnt signaling results in the cessation of apoptosis-induced cell division, highlighting the importance of these signals in tissue maintenance (Brock et al., 2019) [2].

Moreover, programmed cell death mechanisms such as apoptosis and necroptosis are intricately linked to tissue homeostasis. Necroptosis, a form of regulated cell death, has been shown to participate in host defense against pathogens and is involved in tissue repair and regeneration. This process can stimulate inflammation, which is crucial for both protective immune responses and the maintenance of tissue integrity (Yin et al., 2024) [3]. Additionally, the concept of immunogenic cell death (ICD) encompasses how certain cell death programs can elicit inflammatory responses that contribute to tissue homeostasis (Yin et al., 2024) [3].

The interplay between cell death and tissue regeneration is also emphasized in the literature, where it is noted that dead cells release a variety of stimuli, including low-molecular-weight molecules and vesicles, which signal neighboring cells to proliferate and differentiate. This communication is vital for maintaining cellular homeostasis and promoting regeneration after injury (Kopeina et al., 2025) [9]. Furthermore, dying cells can modify the physical characteristics of the tissue, thereby facilitating the elimination of dysfunctional cells and creating a conducive environment for regeneration (Kopeina et al., 2025) [9].

The messenger functions of cell death are increasingly recognized, with studies indicating that the remnants of dying cells can communicate with living cells to influence their fate. This "after-death" signaling can support tissue homeostasis by modulating the responses of neighboring cells, thus contributing to the overall health of the tissue (Lee & Overholtzer, 2019) [18].

In summary, cell death is not merely a process of cellular elimination; rather, it serves as a regulatory mechanism that is essential for maintaining tissue homeostasis. Through various signaling pathways and the release of specific signals, cell death orchestrates a balance between cell loss and regeneration, thereby ensuring the proper functioning of tissues. This intricate relationship underscores the importance of understanding the molecular and cellular dynamics of cell death in the context of tissue maintenance and regeneration.

4.2 Tissue Repair Mechanisms Following Injury ​

Cell death plays a crucial role in regulating tissue homeostasis through various mechanisms that facilitate tissue remodeling, renewal, and repair following injury. The intricate relationship between cell death and tissue homeostasis is underscored by the fact that cell death is not merely a destructive process but also a signaling event that triggers specific responses in surrounding cells.

Cell death can occur through different modalities, including programmed cell death (such as apoptosis) and regulated forms like pyroptosis and necroptosis. Each of these types of cell death initiates distinct signaling cascades that impact neighboring cells and the overall tissue environment. For instance, Rothlin and Ghosh (2020) describe how cell death during morphogenesis and under homeostatic conditions elicits specialized responses from adjacent living cells, which are essential for sculpting tissues and maintaining functionality [19].

Moreover, dying cells can serve as sources of physical or chemical signals that inform surrounding tissues of their status. Fort (2023) emphasizes that the recognition of these signals is critical for the adaptive responses of neighboring cells, allowing them to functionally adapt to changes in their environment. This communication network among cells is vital for maintaining tissue integrity and function, particularly during developmental and homeostatic processes [1].

In the context of injury, cell death can activate repair mechanisms. Zheng et al. (2025) highlight that after spinal cord injury, regulated cell death types such as pyroptosis and ferroptosis can exacerbate inflammation, while autophagy plays a dual role by promoting cell survival and tissue repair. This complex interplay of signaling pathways influences both the deterioration of damaged tissue and the activation of repair processes, indicating that targeted modulation of these pathways may enhance recovery after injury [20].

Additionally, the mechanisms of cell death can impact tissue homeostasis through their after-death functions. Lee and Overholtzer (2019) discuss how remnants of dead cells can support tissue homeostasis, suggesting that the disposal of dead cells and the subsequent responses of the remaining cells are integral to maintaining physiological balance [18].

In summary, cell death signaling regulates tissue homeostasis by triggering specific responses that promote tissue remodeling, communicate vital information to neighboring cells, and activate repair mechanisms following injury. Understanding these processes provides insights into potential therapeutic strategies aimed at enhancing tissue repair and managing diseases associated with dysregulated cell death.

4.3 Immune System Regulation and Inflammation ​

Tissue homeostasis is a dynamic process that involves the regulation of cell survival, proliferation, and death. Cell death signaling plays a crucial role in maintaining this balance, particularly through mechanisms such as apoptosis, necroptosis, and other forms of regulated cell death. Recent studies have elucidated how these processes contribute to tissue homeostasis, immune system regulation, and inflammation.

Cell death is not merely a means to eliminate damaged or unwanted cells; it serves as a vital signaling mechanism that influences the behavior of neighboring cells. For instance, dying cells can release various signals that prompt surrounding healthy cells to proliferate and differentiate, thereby facilitating tissue maintenance and regeneration. In the context of epithelial tissues, apoptotic bodies generated from dying cells can stimulate adjacent stem cells to activate Wnt signaling pathways, leading to increased cellular turnover and maintenance of tissue integrity [2].

Necroptosis, a form of programmed cell death distinct from apoptosis, has been identified as a significant player in immune responses and tissue homeostasis. This form of cell death can elicit inflammatory responses, which are crucial for defending against pathogen infections. However, while necroptosis can protect against infections, it can also contribute to tissue damage if not tightly regulated [3]. The balance between protective and damaging effects of necroptosis is critical, as excessive inflammation can lead to chronic tissue injury and various pathologies.

Moreover, the interplay between different forms of cell death is essential for maintaining tissue homeostasis. For example, in the context of the nervous system, cell death processes are involved in neurogenesis and the response to injuries. The removal of dead or dysfunctional cells allows for the regeneration of healthy tissue, which is vital for recovery after injury [21]. However, disturbances in the balance of cell death and proliferation can lead to diseases, including neurodegenerative conditions and cancers [9].

Cell death signaling also influences immune system regulation. The clearance of apoptotic cells by phagocytes is essential for preventing excessive inflammation and promoting an anti-inflammatory environment. This process not only removes dying cells but also provides signals that can modulate the activity of immune cells, thus ensuring a balanced immune response [18]. For instance, transforming growth factor (TGF)-β signaling has been shown to induce apoptosis in certain cell types while simultaneously promoting the phagocytic clearance of these cells, thereby preventing inflammation and facilitating tissue homeostasis [7].

In summary, cell death signaling is intricately linked to tissue homeostasis through its roles in regulating cell turnover, modulating immune responses, and maintaining the balance between cell death and proliferation. The complex interplay of these mechanisms highlights the importance of cell death not only as a terminal event but as a regulatory process that influences the health and functionality of tissues across various biological contexts. Understanding these processes further can pave the way for therapeutic strategies aimed at restoring tissue homeostasis in diseases characterized by dysregulated cell death and inflammation.

5 Dysregulation of Cell Death and Disease ​

5.1 Cancer: Evasion of Apoptosis ​

Cell death signaling plays a crucial role in maintaining tissue homeostasis by regulating the balance between cell proliferation and cell death. Apoptosis, the intrinsic program of cell death, is a key mechanism through which this balance is achieved. In healthy tissues, a finely tuned equilibrium exists between cell survival and death, ensuring that damaged or superfluous cells are eliminated while allowing for normal growth and tissue regeneration. This regulation is vital for preventing uncontrolled cell proliferation, which can lead to tumor formation [22][23].

The dysregulation of apoptotic signaling pathways can result in a range of pathological conditions, particularly cancer. Tumor cells often acquire mutations that allow them to evade apoptotic signals, leading to excessive cell survival and proliferation. This evasion of apoptosis is considered one of the hallmarks of cancer, as it disrupts the normal homeostatic processes that would otherwise eliminate abnormal cells [24]. For instance, alterations in the expression of key regulators of apoptosis, such as anti-apoptotic proteins (e.g., Bcl-2) and pro-apoptotic factors (e.g., p53), contribute to the survival of cancer cells in unfavorable conditions [25].

Moreover, cancer therapies, including chemotherapy and radiation, primarily function by inducing apoptosis in malignant cells. The effectiveness of these treatments is heavily reliant on the intactness of apoptotic signaling pathways within the cancer cells. When these pathways are compromised, cancer cells may resist the effects of treatment, leading to therapeutic failure [26][27]. Understanding the mechanisms through which cancer cells evade apoptosis not only sheds light on tumorigenesis but also highlights potential therapeutic targets for improving cancer treatment outcomes [28][29].

In summary, the regulation of cell death signaling is essential for maintaining tissue homeostasis, and its dysregulation is a significant contributor to cancer development and progression. The ability of cancer cells to evade apoptosis disrupts the delicate balance required for normal cellular function and contributes to the challenges faced in effective cancer therapy. Thus, insights into the apoptotic pathways and their regulatory mechanisms are critical for developing new therapeutic strategies aimed at restoring the apoptotic response in cancer cells [27][30].

5.2 Neurodegenerative Diseases: Excessive Cell Death ​

Cell death signaling plays a critical role in regulating tissue homeostasis through a delicate balance of cell proliferation, differentiation, and apoptosis. In multicellular organisms, the processes of cell division, differentiation, and programmed cell death (apoptosis) are essential for maintaining tissue integrity and function. Disruption in these processes can lead to a range of diseases, particularly neurodegenerative diseases characterized by excessive cell death.

Cellular homeostasis is maintained by various signaling pathways that regulate the cell cycle and cell death. The integrity of the genome, cell growth, and survival are all influenced by a complex network of regulatory pathways, where cell cycle checkpoints and programmed cell death are paramount. Dysregulation of these pathways can result in uncontrolled cell proliferation or excessive cell death, contributing to diseases such as cancer and neurodegenerative disorders (Wiman & Zhivotovsky, 2017)[31].

In the context of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, excessive cell death is a prominent feature. Neuronal tissues exhibit low regenerative capacity and are particularly vulnerable to disruptions in homeostasis, which can trigger cell death through various pathways, including apoptosis and necroptosis. The activation of these cell death pathways is often associated with the accumulation of misfolded proteins, mitochondrial dysfunction, and oxidative stress, which collectively lead to neuronal degeneration (Motaln & Rogelj, 2023)[32].

Moreover, specific organelles and stress sensors have been identified as potential therapeutic targets in neurodegenerative diseases. For instance, the mitochondria play a crucial role in maintaining cellular homeostasis, and their dysfunction can lead to apoptosis through the release of apoptogenic factors and the activation of signaling proteins involved in cell death pathways (Viana et al., 2010)[33]. The interplay between various forms of cell death, such as apoptosis and necroptosis, also highlights the complexity of cell signaling in neurodegeneration. Necroptosis, a caspase-independent form of cell death, has been implicated in several neurodegenerative conditions and may serve as a potential target for therapeutic intervention (Shao et al., 2017)[34].

The understanding of cell death mechanisms is essential for developing novel therapeutic strategies aimed at mitigating excessive cell death in neurodegenerative diseases. Recent advances suggest that modulating cell death pathways could not only slow the progression of these diseases but also enhance tissue regeneration and recovery (Kopeina et al., 2025)[9]. As research continues to elucidate the molecular mechanisms underlying cell death and its regulation, there is potential for new treatments that could restore homeostasis and improve outcomes for patients suffering from neurodegenerative disorders.

5.3 Autoimmune Disorders: Inflammation and Tissue Damage ​

Cell death signaling plays a crucial role in regulating tissue homeostasis by ensuring a balance between cell survival and cell death, which is essential for maintaining normal physiological functions. Dysregulation of these processes can lead to various diseases, including autoimmune disorders, where inflammation and tissue damage become prevalent.

Apoptosis, or programmed cell death, is a key mechanism in maintaining tissue homeostasis. It is vital for the development and homeostasis of lymphocytes, and disruptions in apoptotic signaling pathways can result in the onset of autoimmune disorders. For instance, the Fas/FasL signaling pathway has been implicated in numerous autoimmune conditions, indicating that alterations in this pathway can lead to inappropriate survival of autoreactive lymphocytes, contributing to tissue damage and inflammation (Prasad and Prabhakar 2003) [35]. Furthermore, the regulation of apoptosis through pathways involving the CD95 (Fas) system is critical; defects in this system have been associated with various lymphoproliferative disorders and autoimmune diseases (Debatin 1996) [10].

In addition to apoptosis, other forms of cell death, such as necroptosis and immunogenic cell death (ICD), also play significant roles in immune responses and tissue homeostasis. Necroptosis, characterized by its inflammatory nature, can stimulate immune responses while also potentially causing tissue damage if not properly regulated (Yin et al. 2024) [3]. The balance between cell death and survival signals is essential; when this balance is disrupted, it can lead to excessive inflammation and tissue injury, as seen in autoimmune diseases.

Moreover, the interaction between dying cells and the immune system is critical for maintaining tissue homeostasis. Dying cells can emit signals that modulate the immune response, influencing whether an immune response is initiated or suppressed (Munoz et al. 2015) [36]. This interaction is particularly important in the context of autoimmune disorders, where the clearance of apoptotic cells and the subsequent immune response can dictate the outcome of inflammation and tissue repair.

The presence of "eat me" signals on dying cells, such as phosphatidylserine, facilitates their clearance by phagocytes, which helps minimize inflammatory responses and prevents the development of autoimmunity (Gaipl et al. 2007) [37]. When this clearance is inefficient, it can lead to the accumulation of apoptotic cells, which may release autoantigens and trigger an autoimmune response.

In summary, the regulation of cell death signaling is pivotal for maintaining tissue homeostasis. Dysregulation of these processes can lead to inadequate clearance of dying cells, inappropriate survival of autoreactive lymphocytes, and excessive inflammation, all of which contribute to the pathogenesis of autoimmune disorders. Understanding these mechanisms is essential for developing targeted therapeutic strategies aimed at restoring the balance of cell death and survival to mitigate tissue damage and inflammation associated with autoimmune diseases.

6 Therapeutic Implications ​

6.1 Targeting Apoptotic Pathways in Cancer Therapy ​

Cell death signaling plays a crucial role in maintaining tissue homeostasis by regulating the balance between cell proliferation and cell death. This balance is essential for normal physiological processes, and any disruption can lead to pathological conditions such as cancer. Apoptosis, a form of programmed cell death, is a key mechanism that ensures the removal of damaged or unwanted cells, thus contributing to tissue integrity and function.

Apoptosis is primarily mediated through two major pathways: the extrinsic pathway, activated by death receptors on the cell surface, and the intrinsic pathway, which is triggered by internal cellular stress signals, such as DNA damage. The execution of apoptosis is primarily carried out by caspases, a family of cysteine proteases that cleave specific substrates to dismantle the cell in a controlled manner. This process culminates in the formation of apoptotic bodies, which are subsequently cleared by phagocytes, thereby preventing inflammation and maintaining tissue homeostasis [38].

In the context of cancer, the dysregulation of apoptosis contributes to tumorigenesis. Cancer cells often acquire mutations that enable them to evade apoptotic signals, allowing for uncontrolled proliferation. This resistance to apoptosis is a significant factor in treatment failure, as many conventional cancer therapies, including chemotherapy and radiation, rely on the induction of apoptosis to eliminate cancer cells [22][23].

The therapeutic implications of targeting apoptotic pathways in cancer therapy are substantial. Understanding the molecular mechanisms that regulate apoptosis can lead to the development of novel therapeutic strategies. For instance, agents that mimic pro-apoptotic signals or inhibit anti-apoptotic proteins (such as Bcl-2) have shown promise in preclinical and clinical settings [39]. Additionally, targeting death receptor pathways with agents like TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) has emerged as a potential therapeutic strategy, as it selectively induces apoptosis in cancer cells while sparing normal cells [40].

Moreover, the interplay between apoptosis and other forms of regulated cell death, such as autophagy and necroptosis, is gaining attention. These pathways can influence each other, and their manipulation may enhance the efficacy of cancer treatments. For example, inhibiting autophagy has been shown to sensitize cancer cells to apoptotic stimuli, thus presenting a combined therapeutic approach [41].

In summary, cell death signaling is integral to maintaining tissue homeostasis, and its dysregulation is a hallmark of cancer. Targeting apoptotic pathways presents a promising avenue for cancer therapy, with the potential to overcome resistance and improve treatment outcomes. Continued research into the complex signaling networks governing cell death will be essential for developing effective and tailored cancer therapies.

6.2 Modulating Necroptosis and Inflammation ​

Cell death signaling plays a crucial role in maintaining tissue homeostasis by regulating the balance between cell survival and death, which is essential for proper physiological functioning and response to stressors. This balance is intricately linked to various forms of cell death, including apoptosis and necroptosis, each contributing differently to tissue integrity and inflammation.

Necroptosis, a programmed form of necrosis, is characterized by its inflammatory nature and distinct signaling pathways involving receptor-interacting protein kinases (RIPK1 and RIPK3) and mixed lineage kinase domain-like protein (MLKL). Recent studies highlight that necroptosis is a significant component of immunogenic cell death (ICD), which can stimulate inflammation and contribute to both protective and pathological outcomes in various conditions, including infections and cancer (Yin et al. 2024) [3]. The inflammatory response triggered by necroptosis is mediated through the release of damage-associated molecular patterns (DAMPs) from dying cells, which can exacerbate tissue damage if not properly regulated (Anderton et al. 2020) [42].

The interplay between necroptosis and inflammation is further elucidated by findings that indicate regulated cell death pathways, including necroptosis, are vital for host defense and tissue homeostasis. For instance, in epithelial tissues, inhibition of necroptosis can prevent excessive inflammation and tissue injury, suggesting that appropriate regulation of this pathway is critical for maintaining barrier integrity and overall tissue health (Kondylis et al. 2017) [43]. In the liver, necroptosis has been identified as a mechanism that contributes to liver diseases, where modulating necroptosis signaling may offer therapeutic avenues for intervention (Ye et al. 2023) [44].

Therapeutically, targeting necroptosis presents a promising strategy for treating various inflammatory and degenerative diseases. For example, inhibiting RIPK1, a key regulator of necroptosis, has shown potential in preventing neuronal cell death and mitigating neuroinflammation in conditions like Alzheimer's disease (Pati et al. 2023) [45]. Furthermore, the development of specific inhibitors of necroptosis is underway, with the goal of regulating its intensity and thus controlling inflammation and tissue damage in diseases such as cardiovascular disorders (Zhe-Wei et al. 2018) [46].

Overall, the regulation of cell death signaling, particularly necroptosis, is essential for maintaining tissue homeostasis and preventing chronic inflammation. The therapeutic modulation of necroptosis not only offers insights into disease mechanisms but also provides a pathway for innovative treatments aimed at restoring balance in tissue homeostasis and managing inflammatory diseases effectively.

6.3 Regenerative Medicine: Harnessing Cell Death Mechanisms ​

Cell death signaling plays a critical role in regulating tissue homeostasis through a delicate balance between cellular proliferation, differentiation, and programmed cell death. This balance is essential for maintaining the integrity and function of tissues, as disruptions can lead to various pathologies, including cancer and degenerative diseases. There are several recognized modes of programmed cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, each of which has distinct roles in tissue regeneration and homeostasis.

Apoptosis, the intrinsic program for cell death, is crucial for regulating tissue homeostasis, particularly in systems with high turnover rates, such as hematopoietic cells. It ensures the elimination of damaged or unwanted cells, thereby preventing tumor formation and maintaining tissue integrity (Debatin et al., 2003). Similarly, necroptosis has emerged as a significant player in immune responses and tissue homeostasis, acting as an immunogenic form of cell death that can stimulate inflammation and enhance host defense against pathogens (Yin et al., 2024). This form of cell death can also impact cancer responses to immunotherapy, highlighting its dual role in both protecting against infections and contributing to tissue damage (Yin et al., 2024).

Ferroptosis, characterized by iron-dependent lipid peroxidation, has gained attention for its implications in aging and age-related disorders. It is particularly relevant in the context of tissue homeostasis, as it can influence cellular senescence and contribute to aging-related tissue dysfunction (De Leon-Oliva et al., 2024). The regulation of these various forms of cell death is essential for maintaining cellular homeostasis and preventing pathological conditions.

The interaction between cell death and tissue regeneration is particularly significant in regenerative medicine. For instance, the balance between cell death and regeneration can dictate the success of stem cell therapies aimed at repairing damaged tissues. Stem cells possess mechanisms that allow them to resist programmed cell death, thereby maintaining their regenerative potential. However, upon transplantation, these cells often face high rates of apoptosis, which can impede their effectiveness in tissue repair (Abdelwahid et al., 2016). Understanding the molecular pathways that regulate stem cell survival and resistance to death signals is crucial for enhancing the efficacy of regenerative therapies.

Therapeutic implications arise from the potential to manipulate cell death pathways to promote tissue regeneration. By harnessing the mechanisms of regulated cell death, it may be possible to develop innovative strategies that enhance stem cell survival and function in regenerative contexts. For example, targeting specific signaling pathways associated with apoptosis and necroptosis could provide new avenues for treating diseases characterized by excessive cell death or insufficient tissue regeneration (Kopeina et al., 2025; Qi et al., 2025).

In conclusion, cell death signaling is integral to maintaining tissue homeostasis and offers significant therapeutic opportunities in regenerative medicine. Advances in understanding the complex interplay between various cell death modalities and tissue regeneration mechanisms could pave the way for novel interventions aimed at enhancing tissue repair and combating degenerative diseases.

7 Conclusion ​

Cell death signaling is integral to the regulation of tissue homeostasis, influencing processes such as cellular turnover, tissue repair, and immune responses. This review highlights the multifaceted roles of various cell death mechanisms, including apoptosis, necroptosis, and autophagy, in maintaining tissue integrity. The findings emphasize that while cell death is often viewed as a detrimental process, it also serves crucial regulatory functions that promote tissue health and regeneration. The interplay between different cell death pathways reveals a complex network of signals that determine cellular fate, underscoring the importance of precise regulation in preventing diseases such as cancer, neurodegenerative disorders, and autoimmune conditions. Future research should focus on elucidating the molecular mechanisms underlying these processes and exploring therapeutic strategies that target cell death pathways to restore tissue homeostasis and enhance regenerative medicine approaches. By understanding how to modulate these pathways effectively, we can develop innovative treatments that address a range of pathological conditions characterized by dysregulated cell death.

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