Herbacetin as a novel therapeutic agent for pulmonary and renal fibrosis by targeting TGFBR2 for degradation.

Rhodiola rosea L. is a traditional Chinese medicine used clinically to treat pulmonary fibrosis. Due to the presence of multicomponents in Rhodiola rosea L., the mechanism of its anti-fibrotic effect remains unclear. Here, we identified that herbacetin from Rhodiola rosea L. is an active molecule with anti-fibrotic effect in two mouse models of bleomycin-induced pulmonary fibrosis and unilateral ureteral obstruction-induced renal fibrosis. We also uncovered the molecular mechanism through which herbacetin exerted its anti-fibrotic effect by inhibiting transforming growth factor beta (TGF-β)/Smad3 signaling. We found that herbacetin could bind to the transforming growth factor beta receptor 2 (TGFBR2) and induced its degradation via the lysosomal pathway following K48-linked ubiquitination, thereby suppressing TGF-β/Smad3 signaling. Thus, herbacetin is a novel anti-fibrotic agent and exerts its anti-fibrotic effect on pulmonary and renal fibrosis by targeting TGFBR2 for degradation.