Key result
NR4A1 limits renal fibrosis in the nucleus but promotes it in the cytoplasm and mitochondria.
Why the study?
Renal fibrosis causes irreversible loss of renal function leading to end-stage renal disease, but effective targeted therapies are currently lacking.
NR4A1 has a dual role in renal fibrosis depending on its subcellular localization, suggesting that stabilizing its nuclear presence could be a novel therapeutic strategy.
NR4A1 bidirectional regulation of renal fibrosis leaves therapeutic targeting unresolved; hypothesis-generating for future studies.
Renal fibrosis is a common pathological process underlying the progression of various kidney diseases to end-stage renal disease. It is characterized by the activation of renal interstitial fibroblasts and excessive deposition of the extracellular matrix (ECM). Continued progression can lead to irreversible loss of renal function, but effective targeted therapies are currently lacking. In recent years, nuclear receptor 4A1 (NR4A1) has been shown to bidirectionally regulate renal fibrosis. Nuclear NR4A1 exerts anti-fibrotic effects by inhibiting pathways such as TGF-β/Smad and NF-κB. However, upon pathological stimulation, NR4A1 translocates to the cytoplasm and mitochondria, where it promotes fibrosis by activating the NLRP3 inflammasome and p38 MAPK signaling and inducing mitochondrial damage. Thus, the functional outcome of NR4A1 is highly dependent on its subcellular localization. This review focuses on the dual anti-fibrotic and pro-fibrotic mechanisms of NR4A1 in renal fibrosis. Based on the regulation of its subcellular localization shifts, we explore targeted intervention strategies aimed at precisely stabilizing its nuclear protective function while blocking pathological nuclear export, thereby providing new directions for treating renal fibrosis.
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Li et al. (2026) conducted a review in Renal fibrosis. NR4A1 was evaluated. NR4A1 exerts a subcellular localization-dependent dual role in renal fibrosis, acting as an anti-fibrotic factor in the nucleus and a pro-fibrotic factor in the cytoplasm and mitochondria.
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