The lysosome as a central executioner: orchestrating multiple modalities of programmed cell death

Lysosomes, long regarded as the cell’s waste disposal system, are now recognized as far more than simple degradative compartments. A comprehensive review published in Frontiers in Cell Death consolidates decades of evidence showing that these organelles function as central signaling hubs that actively orchestrate multiple forms of programmed cell death. The authors, Haonan Yang, Wenqing Ren, and Zhenyu Cai of Tongji University Cancer Center and the Department of Biochemistry and Molecular Biology at Tongji University School of Medicine in Shanghai, propose a unified paradigm in which lysosomes translate diverse stress inputs into specific cell death outputs, fundamentally reshaping how scientists understand cellular fate decisions.

Since their discovery in the 1950s, lysosomes have been defined as cytoplasmic organelles that mediate the degradation of intracellular biomacromolecules, damaged cellular components, and redundant subcellular structures through endocytic, autophagic, or phagocytic pathways. Over seven decades, this understanding has triggered a profound paradigm shift, moving from viewing lysosomes as mere cellular janitors to recognizing them as intricate signaling platforms essential for life. By sensing luminal macromolecules, lysosomes integrate diverse signaling cascades that regulate interorganellar communication, metabolic homeostasis, and immune responses. This signaling capacity is exemplified by key nutrient-sensing pathways such as mTORC1 and AMPK, whose activation status is tightly regulated at the lysosomal surface. Consequently, lysosomes have emerged as central hubs that not only maintain cellular homeostasis but also actively orchestrate cell fate decisions.

Programmed cell death is an actively initiated, highly ordered cellular process tightly governed by genetic programs in multicellular organisms. This biological process is indispensable for growth and development, maintenance of tissue homeostasis, and efficient elimination of damaged or harmful cells. Major modalities include apoptosis, necroptosis, pyroptosis, and ferroptosis, each defined by distinct molecular features. Emerging evidence now positions lysosomes as critical executors in these pathways. Beyond their degradative functions, lysosomes actively participate in cell death signaling through multiple mechanisms. For example, partial lysosomal membrane permeabilization triggers cathepsin leakage into the cytosol, initiating both caspase-dependent and independent apoptotic pathways. In ferroptosis, lysosomes contribute to iron accumulation via ferritin degradation through lysosomal hydrolases and the autophagy pathway. Lysosomal dysfunction and impaired autophagic flux sensitize cells to necroptosis and pyroptosis, underscoring the organelle’s regulatory role in inflammatory cell death.

At the heart of this regulatory capacity lies lysosomal membrane permeabilization, or LMP, a critical event in cellular dysfunction that results in the release of cathepsins and other hydrolases into the cytosol, thereby activating cell death pathways. LMP is implicated in various pathologies, including neurodegenerative diseases, cancer, and autoimmunity. Among the inducers of LMP, reactive oxygen species are the most extensively investigated. Oxidative stress and Fenton chemistry serve as the core endogenous drivers of this process. Lysosomes inherently lack antioxidant enzymes and feature an intraluminal environment enriched with iron ions and oxidizable lipids, rendering them exquisitely vulnerable to oxidative damage. Upon diffusion into the lysosomal lumen, excess hydrogen peroxide reacts with ferrous iron via Fenton chemistry to generate highly reactive hydroxyl radicals. These radicals directly attack unsaturated fatty acids within the lipid bilayer, initiating a chain reaction of lipid peroxidation that alters membrane fluidity and integrity, thereby forming leaks. Consequently, mitochondrial dysfunction or lysosomal dysfunction leading to iron overload directly compromises lysosomal stability.

Physicochemical stress resulting from the accumulation of undegraded materials constitutes another key endogenous cause of LMP. At the endogenous level, impaired cellular clearance capacity or metabolic defects lead to the accumulation of various substrates within lysosomes. Protein aggregates such as amyloid-beta and alpha-synuclein in neurodegenerative diseases can physically rupture the lysosomal membrane from within. Undegraded lipids, such as sphingomyelin and ceramide in lysosomal storage disorders, alter membrane composition chemically: the conical shape of ceramide induces negative curvature stress, directly increasing membrane permeability. Moreover, sphingosine generated from aberrant sphingolipid metabolism becomes enriched in the acidic lysosomal lumen through proton trapping, and its amphipathic structure confers detergent-like activity in acidic environments, enabling direct insertion into and disruption of the lipid bilayer. This inside-out physicochemical disruption mirrors the mechanism by which internalized exogenous particles, such as silica crystals or asbestos fibers, mechanically perforate the lysosomal membrane from within due to their sharp morphology. Certain pathogens can also disrupt membrane stability by interfering with lipid metabolism, as mycobacterial sulfolipids competitively bind host NOD2 protein and the neuraminidase of H5N1 influenza virus degrades the glycosylation of LAMP1, disrupting the protective glycocalyx layer on the membrane surface.

Destabilization of lysosomal membrane integrity constitutes the structural foundation for LMP, with calcium homeostasis imbalance triggering degradation of the membrane scaffold. As an intracellular calcium store, lysosomal membrane stability relies on the integrity of structural proteins such as LAMP2. Aberrant elevation of cytosolic calcium activates calpain, which translocates to the lysosomal membrane and cleaves LAMP2, leading to loss of lysosomal membrane integrity and subsequent cathepsin B leakage and cell death. Calpain can also cleave the membrane-stabilizing protein Hsp70.1, abolishing its protection of the lipid bilayer and rendering the membrane more susceptible to oxidative injury. These processes form a positive feedback loop involving ion leakage, structural degradation, and oxidative stress. Within programmed cell death signaling pathways, death effector proteins can directly target the lysosomal membrane. BAX has been demonstrated to regulate LMP through multiple mechanisms, including in a Parkinson’s disease model where it translocates to the lysosomal membrane at an early stage, forming channel-like structures that directly mediate permeabilization. In TNF-induced necroptosis, activated MLKL forms multimers on the lysosomal membrane, disrupting membrane integrity through altered membrane tension or pore formation.

Dysregulation of pH and enzymatic homeostasis represents the fundamental basis for LMP. The functional integrity of the v-ATPase proton pump is essential for maintaining the acidic lysosomal environment and enzyme activity. Impairment of v-ATPase function or dysregulation of the proton efflux channel TMEM175 leads to elevated intraluminal pH, which not only directly inhibits hydrolase activity but also indirectly affects membrane stability and fusion capacity with other organelles. Exogenous lysosomotropic agents, such as chloroquine, become protonated and trapped, not only directly elevating pH but also inducing osmotic swelling due to the accumulation of charged molecules, leading to physical rupture. The VepA toxin secreted by Vibrio parahaemolyticus directly targets and disrupts the v-ATPase complex, precisely attacking a core component maintaining internal environment homeostasis. The envelope protein of SARS-CoV-2 can act as a proton channel, reducing lysosomal acidity and indirectly compromising membrane stability to facilitate viral escape.

Having established the mechanisms of LMP, the review systematically examines how lysosomes regulate distinct forms of programmed cell death. In apoptosis, cathepsin B released following LMP specifically cleaves the BH3-interacting domain death agonist, generating its proapoptotic truncated fragment tBid, which in turn induces oligomerization of Bcl-XL, a member of the B-cell lymphoma-2 protein family. The resulting oligomeric complexes are directionally translocated to the outer mitochondrial membrane, where they trigger aberrant and excessive opening of the mitochondrial permeability transition pore. MPTP opening facilitates the release of cytochrome c from the mitochondrial intermembrane space into the cytoplasm, where it assembles with Apaf-1 and procaspase-9 to form the apoptosome, activating caspase-9 and subsequently the downstream effector caspase-3. In addition to regulating the Bcl-2-mitochondria pathway, cathepsins can directly target caspases to modulate apoptotic signaling. Cathepsin B cleaves procaspase-2, generating an active fragment that potently induces the release of cytochrome c from mitochondria, contributing to hepatic injury and fibrosis in a mouse model of cholestatic liver disease. During bacterial infection and septic shock, cathepsin D directly activates caspase-8 through a death receptor-independent pathway in neutrophils, triggering downstream effector caspases and initiating apoptosis to facilitate the resolution of inflammation.

In necroptosis, a lytic form of programmed cell death characterized by organelle swelling, plasma membrane rupture, and the subsequent release of intracellular contents, lysosomes play a pivotal regulatory role. LMP, cathepsin release, and calpain-mediated lysosomal damage establish a positive feedback loop with the core necroptotic machinery. Granulysin-induced LMP leads to cathepsin B release, which then cleaves BID to trigger mitochondrial damage and amplify necroptosis. In dendritic cells, polyinosinic-polycytidylic acid induces cathepsin D release via LMP, and this released cathepsin D cleaves caspase-8 at the mitochondrial IPS-1 platform, thereby relieving its inhibition of RIPK1 and RIPK3 and promoting RIPK1 K63-linked polyubiquitination and activation. The functional relevance of these cathepsins is further supported by pharmacological evidence, as combined inhibition of cathepsin B and cathepsin D completely abrogates necroptosis, underscoring their cooperative and essential roles. Calpains function as key upstream regulators of LMP during necroptosis, closely linked to calcium dynamics, and calpain inhibitors markedly reduce the incidence of necroptosis. In pyroptosis, lysosomes play a dual regulatory role, acting as both an executor of non-classical pyroptosis and an amplifier of the classical pathway, with cathepsin B and cathepsin D identified as core regulatory molecules. Lysosomal injury triggers inflammasome assembly through multiple pathways, including the release of cathepsins and ionic signals such as calcium flux activating CaMKII and potassium efflux activating the NLRP3 inflammasome.

In ferroptosis, lysosomes serve as central regulatory hubs through three core mechanisms: acting as the primary intracellular iron reservoir, mediating lipid peroxidation-induced LMP, and regulating ferritinophagy to precisely control labile iron levels. The acidic lysosomal lumen harbors the highest cellular concentration of labile ferrous iron, making it a primary site for Fenton reaction-driven ROS generation during ferroptosis. Early lipid peroxidation in ferroptosis originates within lysosomes, with the ferroptosis inducer RSL3 initiating membrane lipid oxidation predominantly in this compartment before propagating to the endoplasmic reticulum. Ferritinophagy, mediated by the cargo receptor NCOA4, delivers ferritin to autophagosomes that fuse with lysosomes, where ferritin is degraded by lysosomal hydrolases including cathepsin B, releasing ferrous iron into the cytoplasm. In autophagic cell death, LMP triggers the release of cathepsins that degrade essential cellular structures and disrupt ion homeostasis, shifting the balance from cytoprotective autophagy to cell death execution. The endosomal sorting complexes required for transport machinery can repair minor lysosomal membrane injuries, but when damage exceeds the repair capacity, lysophagy is triggered, ultimately culminating in autophagic cell death. These interconnected pathways reveal that LMP acts as a central hub orchestrating crosstalk among apoptosis, pyroptosis, ferroptosis, necrosis, and autophagic cell death, refining cell death classification and providing a therapeutic rationale for targeting lysosomes in cancer, neurodegeneration, and chronic inflammation.

Subject of Research: The lysosome as a central executioner: orchestrating multiple modalities of programmed cell death

Article Title: The lysosome as a central executioner: orchestrating multiple modalities of programmed cell death

Article References: Yang, H., Ren, W., & Cai, Z. (2026). The lysosome as a central executioner: orchestrating multiple modalities of programmed cell death. Frontiers in Cell Death, 5, Article 1841940. https://doi.org/10.3389/fceld.2026.1841940

Image Credits: AI Generated

DOI: 10.3389/fceld.2026.1841940

Keywords: lysosome, central, executioner, orchestrating, multiple, modalities, programmed, cell, death, scientific research