Lactate orchestrates the TGFβ pathway and ferroptosis nexus in organ fibrosis via USP2 lactylation

TGFβ1 and ferroptosis are key drivers of organ fibrosis, but their crosstalk remains unclear. This study aims to identify the key regulatory ubiquitin-specific protease (USP) in organ fibrosis, TGFβ signaling transduction, and ferroptosis. Here, we show that global or renal tubule-specific deletion of Usp2 ameliorates kidney fibrosis in UUO models of male mice, while kidney tubule-specific Usp2 overexpression exacerbates fibrosis and reverses the protective effect conferred by global Usp2 deletion. Mechanistically, USP2 deubiquitinates TXNDC5, an ER protein that stabilizes TGFβR1 to activate TGFβ signaling. USP2 also deubiquitinates the transferrin receptor (TFRC), enhancing TFRC's role in promoting ferroptosis. TGFβ1 lactylates USP2 at Lys447 to facilitate deubiquitination of TXNDC5 and TFRC, whereas SIRT2 delactylates USP2 at Lys447 to suppress its activity. Notably, the USP2 inhibitor ML364 alleviates fibrosis in male mouse models of kidney, liver, and lung mouse models. Our findings establish USP2 as a key regulator of the TGFβ pathway and ferroptosis, highlighting its potential as a therapeutic target for fibrosis.