Isoform-specific roles of SKN-1/Nrf in Caenorhabditis elegans longevity via mTOR signaling.

Abstract

SKN-1, a Cap'n'Collar transcription factor in Caenorhabditis elegans, is a well-established regulator of oxidative stress responses and xenobiotic detoxification. Over the past two decades, the late Dr. T. Keith Blackwell (1957-2025) and colleagues made seminal contributions to defining its biological functions and regulatory mechanisms. Owing to its robust conservation with mammalian Nrf family proteins, SKN-1 research has yielded fundamental insights into how nutrient and stress signals modulate metabolism, proteostasis, and aging. Recently, the discovery that distinct SKN-1 isoforms execute unique physiological roles has further refined this field. In this review, we summarize how SKN-1 regulates longevity, particularly through the mTOR nutrient-sensing pathway, discuss recent advances in isoform-specific regulation, and highlight critical questions for future research.