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STK40 inhibits profibrotic Arg1+ macrophage differentiation and renal fibrosis by regulating poly-ubiquitination of STAT3
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DOI：10.1038/s41401-026-01893-8.png)
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Abstract
En 中文
Monocyte-derived macrophages are central drivers of chronic renal inflammation and fibrosis, yet the regulatory mechanisms that restrain their profibrotic differentiation remain poorly defined. Here, we identified serine/threonine kinase 40 (STK40) as a suppressor of profibrotic macrophage differentiation and renal fibrosis progression. Myeloid-specific Stk40 deletion exacerbated renal fibrosis in multiple mouse models. Single-cell RNA sequencing revealed expansion of Arg1⁺ macrophages in STK40-deficient kidneys. In vitro, STK40 restrained the differentiation of profibrotic Arg1⁺ macrophages in a constitutive photomorphogenic protein 1 (COP1)-dependent manner. Functionally, Arg1⁺ macrophages were potent extracellular matrix (ECM)-producing cells and promoted renal fibrosis both directly, through cell-intrinsic macrophage-to-myofibroblast transition (MMT), and indirectly, by inducing epithelial–mesenchymal transition (EMT). STK40 loss led to aberrant STAT3 activation, whereas pharmacological inhibition of STAT3 attenuated excessive profibrotic differentiation of STK40-deficient bone marrow-derived macrophages (BMDMs). Mechanistically, STK40 functioned as an adaptor linking COP1 and STAT3, thereby promoting STAT3 poly-ubiquitination. Finally, oral administration of an Arg1-targeted small-molecule inhibitor rescued renal fibrosis exacerbated by myeloid Stk40 deficiency. These findings define an STK40–COP1–STAT3 axis that restrains profibrotic Arg1⁺ macrophage differentiation and identify Arg1⁺ macrophages as a potential therapeutic target for chronic kidney disease with progressive renal fibrosis.
Keywords:
STK40
renal fibrosis
Arg1+ macrophage
COP1
STAT3
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