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 acids responsible for this benefit and its underlying mechanism remain unclear. Using exclusively male mice throughout this study, we screen 15 amino acid–restricted diets in a unilateral ureteral obstruction model and identify methionine restriction (MetR) as the most effective intervention. Integrating transcriptomic and cistromic analyses identify Hoxc8 as a central pro-fibrotic transcription factor downstream of TGF-β–Smad3 signaling. Hoxc8 reinforces its own expression and drives fibrotic gene programs through recruitment of the P-TEFb transcriptional elongation complex. HOXC8 is elevated in fibrotic human kidneys, and fibroblast-specific Hoxc8 deletion protects mice from renal fibrosis. MetR suppresses this pro-fibrotic circuit by reducing active histone marks at the Hoxc8 locus, thereby attenuating Hoxc8-dependent transcription. Together, these findings identify the TGF-β–Smad3–Hoxc8/P-TEFb axis as a key driver of renal fibrosis and highlight MetR as a promising therapeutic strategy. Limiting dietary methionine protects against kidney fibrosis by blocking the TGF-β– Smad3–Hoxc8/P-TEFb pathway, identifying Hoxc8 as a central driver of fibrosis and a potential therapeutic target for chronic kidney disease.