Senescent cells are cells that have permanently stopped dividing, often in response to DNA damage or stress. Rather than simply retiring quietly, they remain metabolically active and secrete a cocktail of proinflammatory molecules known as the senescence-associated secretory phenotype, or SASP. While this process plays a role in wound healing and tumor suppression in the short term, the gradual accumulation of senescent cells in tissues drives chronic inflammation and has been implicated in conditions ranging from frailty and diabetes to liver fibrosis and cancer. Eliminating these cells, an approach called senolysis, has therefore become one of the most actively pursued strategies in geroscience.

The problem, according to the research team led by Jianghao Qian and Akiko Takahashi, is that most current senolytic drugs work by targeting antiapoptotic pathways that senescent cells deploy to avoid self-destruction. These drugs, including the best-known combination of dasatinib and quercetin, can be effective but carry dose-dependent toxicity that limits their clinical utility. The Japanese team set out to find a fundamentally different way to kill senescent cells, and their search led them to an unexpected candidate: a forty-year-old immunosuppressant sitting in hospital pharmacies around the world.

Their findings reveal that cyclosporine A kills senescent cells through paraptosis-like cell death, a caspase-independent process that does not rely on the conventional apoptosis machinery targeted by existing senolytics. In paraptosis, cells die through dramatic swelling and vacuolization of the endoplasmic reticulum and mitochondria rather than through the orderly fragmentation characteristic of apoptosis. Using live-cell holotomography imaging, the researchers directly visualized this distinctive death process unfolding in senescent cells treated with the drug.

The mechanism behind this selectivity is elegant in its exploitation of a senescent cell’s own weakness. The team discovered that cyclosporine A activates JNK signaling and elevates production of reactive oxygen species, which in turn triggers the apoptosis signal-regulating kinase 1, or ASK1, and its downstream partner, the p38 mitogen-activated protein kinase pathway. Rather than suppressing inflammation as it does in immune cells, the drug amplifies SASP factor expression in senescent cells, dramatically increasing their secretory output.

This SASP overactivation turns out to be lethal precisely because senescent cells are already operating at the limit of their protein-handling capacity. The researchers showed that senescent cells inherently exhibit chronic adaptive endoplasmic reticulum stress responses and heightened ER functional demands, a direct consequence of their extensive secretory activity. The endoplasmic reticulum is the cellular organelle responsible for folding and processing the vast majority of secreted proteins, and the constant flood of inflammatory SASP factors places an enormous burden on this system. When cyclosporine A further disrupts this fragile ER homeostasis by forcing SASP overexpression, the organelle swells catastrophically, and the cell succumbs to paraptosis-like death.

In other words, the very trait that makes senescent cells harmful to tissue, their relentless secretion of inflammatory mediators, becomes the vulnerability that cyclosporine A exploits. Healthy nonsenescent cells, which do not carry this chronic ER stress burden, tolerate the drug at concentrations that prove lethal to their senescent counterparts, providing a mechanistic basis for the drug’s selectivity.

The therapeutic implications were tested directly in an animal model of obesity-associated liver cancer. Obese mice accumulate senescent hepatic stellate cells in their livers, and these cells promote the development of hepatocellular carcinoma by sustaining the inflammatory microenvironment that feeds tumor growth. When the researchers treated obese mice with cyclosporine A, the drug eliminated the senescent stellate cells from the liver and, remarkably, prevented the development of obesity-associated hepatocellular carcinoma. This finding suggests that senolysis via paraptosis could be deployed not merely to slow aging but to intervene in specific cancers driven by senescent cells in the tumor microenvironment.

The study represents a significant conceptual expansion of the senolytic toolkit. By demonstrating that ER stress-induced paraptosis-like cell death can serve as a viable senolysis strategy, the work establishes an entirely new mechanistic class of senotherapy, one that targets the proteostatic fragility of senescent cells rather than their apoptotic defenses. Because cyclosporine A is already an approved clinical drug with well-characterized pharmacology, the path from bench to bedside could be considerably shorter than for entirely novel compounds, although the researchers caution that dose, duration, and the drug’s immunosuppressive effects will all need careful evaluation in the context of senotherapy.

More broadly, the findings add to a growing recognition that aging cells can be eliminated by exploiting metabolic and stress-response vulnerabilities unique to their state. If ER stress amplification proves safe and effective in humans, the strategy could eventually be applied across a broad spectrum of age-related disorders, from fibrotic liver disease to inflammation-driven tumors, offering a way to turn a decades-old transplant drug into a weapon against the biology of aging itself.

Subject of Research: Senolysis via cyclosporine A-induced endoplasmic reticulum stress and paraptosis-like cell death in senescent cells

Article Title: Cyclosporine A provokes paraptosis-like cell death in senescent cells by triggering endoplasmic reticulum stress

Article References: Qian, J., Zhou, X., Lee, K.-S., Loo, T. M., Tanaka, Y., Sugawara, S., Hanyu, A., Kawasaki, H., Yotsumoto, S., Dodo, K., Shirasaki, Y., Kamatani, T., Tanaka, K., & Takahashi, A. (2026). Cyclosporine A provokes paraptosis-like cell death in senescent cells by triggering endoplasmic reticulum stress. Genome Biology. https://doi.org/10.1186/s13059-026-04273-x

Image Credits: AI Generated

DOI: 10.1186/s13059-026-04273-x

Keywords: cellular senescence, senolysis, cyclosporine A, endoplasmic reticulum stress, paraptosis, SASP, hepatocellular carcinoma, aging, cell death, senolytics, Cyclosporine, provokes