Nunez-Quintela, V. | Search bioRxiv

bioRxiv2026

SENOMORPHIC EFFECT OF GENETIC AND CHEMICAL PARTIAL REPROGRAMMING

Partial reprogramming has emerged as a promising strategy to ameliorate aging phenotypes, yet its cellular targets and mechanisms remain poorly defined. Cellular senescence is a central hallmark of aging and a plausible mediator of reprogramming-induced rejuvenation. Here we show that genetic and chemical partial reprogramming act directly on senescent cells without restoring proliferative capacity. OSKM expression or a reduced two-compound regimen, tranylcypromine and RepSox (2c), attenuates senescence-associated secretory activity, restores mitochondrial homeostasis and apoptotic priming, and improves functional and inflammatory parameters in aged mice, establishing senomorphic, identity-preserving reprogramming as a potentially safer aging intervention.

cell biology↗

bioRxiv2023

Failed reprogramming of transformed cells due to induction of apoptosis and senescence impairs tumor progression in lung cancer

Cell reprogramming to pluripotency applied to the study of cancer has identified transformation and pluripotency as two independent and incompatible cell fates. A detailed knowledge of the relationship between transformation and reprogramming could lead to the identification of new vulnerabilities and therapeutic targets in cancer. Here, we explore this interplay and find that OSKM expression limits tumor cell growth by inducing apoptosis and senescence. We identify Oct4 and Klf4 as the main individual reprogramming factors responsible for this effect. Mechanistically, the induction of cell cycle inhibitor p21 downstream of the reprogramming factors acts as mediator of cell death and senescence. Using a variety of in vivo systems, including allografts, orthotopic transplantation and KRAS-driven lung cancer mouse models, we demonstrate that OSKM expression impairs tumor growth and reduces tumor burden.

cell biology↗