In a groundbreaking study poised to redefine therapeutic strategies for non-small cell lung cancer (NSCLC), researchers have unveiled the potent antitumor efficacy of fosinopril, a drug typically prescribed for cardiovascular conditions, by elucidating its novel mechanism of inducing GSDME-dependent pyroptosis. This revelation opens an innovative avenue in cancer therapy, where a widely used antihypertensive agent is repurposed to trigger a distinct form of programmed cell death, disrupting malignancy in NSCLC—a subtype notoriously resistant to conventional treatments.
NSCLC remains one of the leading causes of cancer-related mortality worldwide, frequently presenting challenges due to resistance to apoptosis, the most commonly targeted cell death pathway in cancer therapies. The discovery that fosinopril induces pyroptosis, rather than apoptosis, marks a significant paradigm shift. Pyroptosis is a form of lytic programmed cell death characterized by cellular swelling, membrane rupture, and inflammatory cytokine release. This form of cell death, mediated through gasdermin family proteins, offers a promising alternative to eradicate cancer cells that evade apoptosis.
Central to this mechanism is gasdermin E (GSDME), a protein that, when cleaved, forms pores in the plasma membrane, leading to cell swelling and lysis. The study meticulously delineates how fosinopril activates caspase proteins, which in turn cleave GSDME, unleashing its pyroptotic function. This process contrasts significantly with the classical apoptosis pathway, where cells undergo controlled dismantling without eliciting inflammation, underscoring an innovative anti-cancer modality that not only kills the tumor cells but potentially activates an immune response against the tumor microenvironment.
The researchers utilized both in vitro and in vivo NSCLC models to validate fosinopril’s efficacy. At the molecular level, they observed increased expression and cleavage of GSDME following fosinopril treatment, correlating with enhanced pyroptotic markers such as cell swelling and lactate dehydrogenase (LDH) release. These pyroptotic events culminated in a marked reduction of tumor cell viability and tumor burden in animal models, suggesting a potent antitumor effect mechanistically linked to pyroptosis induction.
Further molecular analyses revealed that fosinopril’s induction of pyroptosis is intricately tied to the activation of upstream caspases, particularly caspase-3, known to bridge apoptotic and pyroptotic pathways by cleaving GSDME. This cleavage releases the GSDME N-terminal domain, which oligomerizes within the plasma membrane, generating pores that rupture the cell membrane, expelling intracellular contents and alerting the immune system. The inflammatory milieu engendered by pyroptosis could synergistically enhance anti-cancer immunity, a feature absent in apoptosis-driven therapies.
This study pioneers the repositioning of fosinopril beyond its conventional role as an angiotensin-converting enzyme (ACE) inhibitor. The molecular crosstalk between the renin-angiotensin system and pyroptotic pathways had remained largely unexplored prior to this investigation. By delineating these unexpected interactions, the authors provide a compelling rationale for clinical trials aiming to harness fosinopril’s dual functions, potentially improving NSCLC outcomes while capitalizing on its known safety profile.
The implications of this research extend deep into the clinical realm, where resistance mechanisms often limit the efficacy of targeted therapies and immunotherapies in NSCLC. Leveraging pyroptosis as a therapeutic endpoint offers a novel mode of action that might circumvent existing resistance and potentiate combination therapies. Moreover, the inflammatory aftermath of pyroptosis could enhance tumor antigen presentation and immunogenicity, possibly converting “cold” tumors resistant to immunotherapy into “hot,” more responsive ones.
Crucially, the researchers also addressed possible off-target effects and toxicity, conducting comprehensive assessments across various non-cancerous cell lines. Their data underscored a favorable therapeutic window where fosinopril selectively triggered pyroptosis in tumorigenic cells with minimal cytotoxicity in normal pulmonary tissues. This selectivity hints at mechanistic nuances within cancer cells’ microenvironment or genetic landscape that sensitize them to GSDME-mediated pyroptosis.
Mechanistically, the study delves into the signaling pathways upstream of caspase activation, uncovering involvement of mitochondrial dysfunction and reactive oxygen species (ROS) generation. Fosinopril treatment resulted in mitochondrial membrane potential disruption, elevating intracellular ROS, which serves as a pro-apoptotic and pyroptotic stimulus. These findings highlight a multifactorial process where fosinopril orchestrates a complex interplay of signals culminating in cancer cell death.
While previous studies have implicated pyroptosis in infectious and inflammatory diseases, its therapeutic exploitation in oncology remains nascent. This research serves as a landmark, suggesting that repurposing classical drugs to exploit this pathway can accelerate translational efforts. The authors propose that targeting GSDME expression or function could be customized to individual patient tumors, tailoring treatments based on the tumor’s molecular profile and pyroptotic susceptibility.
The study also explored synergistic potential by combining fosinopril with existing chemotherapeutic agents. Preliminary data indicated enhanced efficacy, possibly through additive or cooperative induction of cell death pathways. This combinatorial approach could mitigate limitations of monotherapy and offer robust therapeutic responses in diverse NSCLC patient populations.
On a broader scale, the ability to induce pyroptosis selectively in tumor cells may herald transformative shifts in cancer immunotherapy. The immunogenic nature of pyroptotic cell demise, characterized by the release of pro-inflammatory cytokines such as IL-1β and IL-18, offers a template for in situ tumor vaccination strategies. Fosinopril may thus serve as a prototype for designing drugs that couple cytotoxicity with immune activation, an intersection critical for durable cancer control.
The researchers also emphasize the need for extensive clinical validation, recognizing that translating these promising preclinical outcomes into effective human therapies will necessitate rigorous pharmacokinetic and pharmacodynamic studies. Variables such as dosage optimization, delivery modalities, and patient stratification based on GSDME expression levels will be pivotal for maximizing therapeutic benefits while minimizing adverse effects.
Moreover, the broader implications for ACE inhibitors in oncology warrant reevaluation, as fosinopril’s anticancer properties could inspire systematic screening of related compounds for pyroptotic activity. This could foster a new class of anti-cancer agents that repurpose existing drugs, thereby shortening development timelines and enhancing patient accessibility.
In conclusion, the study by Gao, Zhai, Zhang, and colleagues represents a quantum leap in lung cancer therapeutics, revealing a previously unrecognized mechanism by which fosinopril exerts antitumor effects via GSDME-dependent pyroptosis. This work not only broadens the mechanistic understanding of cancer cell death but also paves the way for innovative, immune-activating treatment strategies against NSCLC, a cancer subtype in urgent need of novel therapeutic options.
Subject of Research: The investigation focuses on fosinopril’s antitumor effects mediated through the induction of gasdermin E (GSDME)-dependent pyroptosis in non-small cell lung cancer (NSCLC).
Article Title: Fosinopril mediates antitumor efficacy by inducing GSDME-dependent pyroptosis in NSCLC.
Article References:
Gao, Y., Zhai, X., Zhang, C. et al. Fosinopril mediates antitumor efficacy by inducing GSDME-dependent pyroptosis in NSCLC. Cell Death Discov. 11, 540 (2025). https://doi.org/10.1038/s41420-025-02791-4
Image Credits: AI Generated
DOI: 21 November 2025
Tags: antitumor effects of fosinoprilcaspase activation in cancer therapyFosinopril for non-small cell lung cancergasdermin family proteins in cancerGSDME-dependent pyroptosisinflammatory cytokine release in pyroptosislytic cell death pathwaysnovel cancer therapy strategiesNSCLC treatment advancementsovercoming apoptosis resistance in cancerprogrammed cell death mechanismstherapeutic repurposing of antihypertensive drugs
