Methionine Restriction Alleviates Kidney Fibrosis through Epigenetic Repression of the TGF-β-Smad3-Hoxc8/P-TEFb axis

Low-protein diets can mitigate renal fibrosis, yet the critical amino acid responsible for this benefit and its underlying mechanism remain unclear. By screening 15 amino acid–restricted diets in a unilateral ureteral obstruction (UUO) model, we identify methionine restriction (MetR) as the most effective intervention. Integrating transcriptomic and cistromic analyses further uncover Hoxc8 as a central pro-fibrotic transcription factor. Hoxc8 is induced by TGF-β–Smad3, amplifies its own expression, and drives fibrotic gene programs through recruitment of the P-TEFb transcriptional elongation complex. Clinically, HOXC8 is elevated in fibrotic human kidneys, and fibroblast-specific Hoxc8 deletion protects mice from fibrosis. MetR attenuates this pro-fibrotic circuit by reducing active histone marks (H3K4me3 and H3K36me3) at the Hoxc8 locus, thereby suppressing the Hoxc8-dependent fibrotic transcriptional program. Together, these findings establish the TGF-β–Smad3–Hoxc8/P-TEFb axis as a key driver of renal fibrosis and highlight MetR as a promising therapeutic strategy.