TRIB3 recruits and stabilizes CARM1 to confer chemoresistance by activating Akt signalling in clear cell renal cancer cells

Sunitinib resistance remains a major obstacle in the treatment of clear cell renal cell carcinoma (ccRCC), yet the underlying mechanisms are poorly defined. Here, we identify a previously unrecognized axis involving Tribbles homolog 3 (TRIB3) and coactivator-associated arginine methyltransferase 1 (CARM1) that drives chemoresistance through modulation of Akt signaling. Mechanistically, TRIB3 directly interacts with CARM1, a pro-survival epigenetic regulator, and inhibits its ubiquitination to stabilize CARM1 protein levels. Elevated CARM1 further exacerbates therapeutic resistance, establishing a feedforward loop that sustains Akt activation. Our findings uncovering a novel TRIB3-CARM1-Akt axis as a central driver of sunitinib resistance. This study provides mechanistic insights into ccRCC chemoresistance and highlights therapeutic targeting of the TRIB3-CARM1 axis as a promising strategy to overcome treatment failure.