Nerve growth factor‐induced gene B (Nur77) has been shown to ameliorate several biological processes in chronic diseases, including inflammatory response, cellular proliferation, and metabolism. Chronic kidney disease (CKD) is characterized by tubulointerstitial fibrosis for which no targeted therapies are available as yet. In this study, we performed in vivo and in vitro experiments to demonstrate that Nur77 targets fibrosis signals and attenuates renal tubulointerstitial fibrosis during the aging process. We observed that the TGF‐β/Smads signal pathway was significantly suppressed by Nur77, suggesting that Nur77 controlled the activation of key steps in TGF‐β/Smads signaling. We further showed that Nur77 interacted with Smad7, the main repressor of nuclear translocation of Smad2/3, and stabilized Smad7 protein homeostasis. Nur77 deficiency resulted in Smad7 degradation, aggravating Smad2/3 phosphorylation, and promoting transcription of its downstream target genes, ACTA2 and collagen I. Our findings demonstrate that Nur77 is a potential therapeutic target for age‐related kidney diseases including CKD. Maintenance of Nur77 may be an effective strategy for blocking renal tubulointerstitial fibrosis and improving renal function in the elderly.

Osteoporosis is a metabolic systemic bone disease that typically manifests as decreased bone mass and increased bone fragility. 1 With the ageing of the worldwide population, the social and economic burdens of osteoporosis remain steady. According to a previous study, approximately 15,000 osteoporotic fractures occur in the United States every year, 2 which not only severely affects patients' quality of life but also imposes heavy burdens on medical and health systems. The currently known risk factors for osteoporosis include age, 3 vitamin D and calcium deficiencies, 4 insufficient exercise, 5 smoking, 6 drinking, 7 oestrogen withdrawal 8 and

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Obesity may impair muscle function and is sometimes associated with lower muscle mass. However, the internal regulatory mechanism is still unclear. Nur77 has been reported to improve obesity phenotype by regulating glucose and lipid metabolism and inhibiting the production of inflammatory factors and reactive oxygen species. Concurrently, Nur77 also plays an important role in muscle differentiation and development. We aimed to investigate the role of Nur77 in obesity‐related lower muscle mass. Our in vivo and in vitro experiments illustrated that the reduction of obesity‐related Nur77 accelerated the occurrence of lower muscle mass by interfering with the signaling pathways involved in the regulation of myoprotein synthesis and degradation. We further demonstrated that Nur77 activates the PI3K/Akt pathway by promoting Pten degradation, which enhances the phosphorylation of the Akt/mTOR/p70S6K pathway and inhibits the expression of skeletal muscle‐specific E3 ligases (MAFbx/MuRF1). Nur77 induces Pten degradation by increasing the transcription of its specific E3 ligase Syvn1. Our study confirms that Nur77 is a key factor in ameliorating obesity‐related lower muscle mass, providing a new therapeutic target and theoretical basis for the treatment of obesity‐related lower muscle mass.

Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that protects against premature aging and cellular senescence. Aging that is accompanied by oxidative stress leads to a decrease in SIRT1 level and activity, but the regulatory mechanism that connects these events has remained unclear. Here we report that Nur77, an orphan nuclear receptor that shares similar biological pathways with SIRT1, also decreases with age in multiple organs. Our in vivo and in vitro studies revealed that Nur77 and SIRT1 decrease during aging and oxidative stress-induced cellular senescence. Deletion of Nur77 shortens lifespan and accelerates the aging process in multiple mouse tissues. Overexpression of Nur77 protects SIRT1 protein from proteasome degradation through negative transcriptional regulation of the E3 ligase murine double minute 2 (MDM2). Our results show that Nur77 deficiency remarkably aggravates aging related nephropathy, and elucidate a key role for Nur77 in the stabilization of SIRT1 homeostasis during renal aging. We propose a model wherein reduction of Nur77 upon oxidative stress promotes SIRT1 protein degradation through MDM2, which triggers cellular senescence. This creates additional oxidative stress and provides positive feedback for premature aging by further decreasing Nur77 expression. Our findings reveal the mechanism of oxidative stress-reduced SIRT1 during aging and offer an attractive therapeutic strategy for targeting aging organism homeostasis.