Deletion of Nrf1α exacerbates oxidative stress-induced cellular senescence by disrupting cell homeostasis

Abstract

Cellular senescence is recognized as a fundamental hallmark contributing to ageing and various age-related diseases, with oxidative stress playing a critical initiating role in their pathological processes. However, the anti-senescence potential of the antioxidant nuclear factor erythroid-derived 2-like 1 (Nrf1, encoded by Nfe2l1) remains elusive, despite accumulating evidence demonstrating its role as an indispensable redox-determining transcription factor for maintaining cellular homeostasis and organ integrity. This study reveals that deletion of Nrf1α significantly elevates senescence characteristics in Nrf1α^−/−-deficient cells, as evidenced by two distinct experimental models. These cells exhibit heightened activity of senescence-associated β-galactosidase and progressive senescence-associated secretory phenotype (SASP), accompanied by decreased cell vitality and intensified cell cycle arrest. Further investigation uncovers that this acceleration of oxidative stress-induced senescence results from increased disturbance in cellular homeostasis. The Nrf1α^−/− deficiency leads to STAG2- and SMC3-dependent chromosomal stability disruption and autophagy dysfunction, albeit being accompanied by excessive accumulation of Nrf2 (encoded by Nfe2l2). The aberrantly hyperactive Nrf2 cannot effectively counteract the escalating disturbance of cellular homeostasis caused by Nrf1α^−/−. This study provides evidence supporting Nrf1α's essential cytoprotective function against stress-induced cellular senescence, highlighting its indispensable contribution to maintaining robust cell homeostasis during the senescence pathophysiological process.