Deletion of Nrf1 exacerbates oxidative stress-induced cellular senescence by disrupting the cell homeostasis

Abstract Cellular senescence has been accepted as a fundamental contributor to ageing and a variety of age-related diseases, in which oxidative stress has been further recognized to play a critical initiation role. However, the anti-senescence potential of antioxidant nuclear factor erythroid-derived 2-like 1 (Nrf1, encoded by Nfe2l1 ) remains elusive to date, even though the hitherto accumulating evidence demonstrates that it is an indispensable redox-determining transcription factor for maintaining cellular homeostasis and organ integrity. Herein, we discovered that deletion of Nrf1 resulted in markedly elevated senescence characteristics in Nrf1α −/− cells, as characterized by two distinct experimental models induced by oxidative stress, which are evinced by typically heightened activity of senescence-associated β-galactosidase and progressive senescence-associated secretory phenotype (SASP), along with decreased cell vitality and intensified cell cycle arrest. Further experimental investigation also uncovered that such acceleration of oxidative stress-induced senescence resulted from heightened disturbance in the cellular homeostasis, because deficiency of Nrf1α leads to the STAG2- and SMC3-dependent chromosomal stability disruption and autophagy dysfunction, though as accompanied by excessive accumulation of Nrf2 (encoded by Nfe2l2 ). The aberrant hyperactive Nrf2 cannot effectively counteract the escalating disturbance of cellular homeostasis caused by Nrf1α −/− . Overall, this study has provided a series of evidence supporting that Nrf1 indeed exerts an essential protective function against oxidative stress-induced cellular senescence, thereby, highlighting its primary indispensable contribution to maintaining robust cell homeostasis.