Hepatokine fibrinogen-like protein 1 drives liver-kidney crosstalk to promote renal fibrosis.

The concept of organ-organ communication in systemic diseases has gained significant traction. Despite accumulating evidence of liver-kidney crosstalk, the underlying regulatory mechanisms remain poorly understood. Here, we identify hepatokine fibrinogen-like protein 1 (FGL1) as a pivotal mediator driving liver-kidney communication in renal fibrosis. Integrative RNA sequencing and clinical analyses revealed FGL1 upregulation in the liver post-renal injury, with subsequent selective accumulation in fibrotic kidneys. Hepatocyte-specific knockout of FGL1 improved renal morphology, attenuated collagen deposition, and inhibited fibrosis markers in unilateral ureteral obstruction and adenine-induced mouse models. Conversely, FGL1 overexpression exacerbated renal fibrosis. Mechanistically, FGL1 binds to TGF-β receptor ALK5 and blocks its interaction with K48-linked polyubiquitin. Structural analyses identified critical residues in FGL1-ALK5 interaction. Hepatic FGL1 is transcriptionally regulated by STAT3, and activated by inflammatory cytokines (IL-6, IL-1β and TNF-α). Pharmacological inhibition by p-hydroxybenzaldehyde (screened out from 4080 compounds) or an anti-FGL1 monoclonal antibody significantly reduced renal fibrosis without hepatotoxicity. These findings establish FGL1 as a key mediator of pathogenic liver-kidney crosstalk and highlights therapeutic strategies to targeting organ-organ networks in renal fibrosis.