Targeting RPL4 improves the therapeutic efficacy of PD-L1 blockade in liver fibrosis.

Activation and progressive accumulation of hepatic stellate cells (HSCs) are pivotal events in the progression of liver fibrosis, and no effective treatments are available to date. Hepatic FBXL6 promotes hepatocarcinogenesis, but the function of FBXL6 in tissue stromal cells remains unknown. Here, FBXL6 is highly expressed in the activated HSCs in human fibrotic livers. HSC-specific FBXL6 overexpression or deletion is achieved by crossbreeding Fbxl6CKI/+ or Fbxl6CKO-fl/+ mice with Pdgfrβ-Cre mice. FBXL6 drives liver fibrosis in mice, whereas FBXL6 deletion attenuates chemical- or MASH-induced liver fibrosis. Mechanistically, FBXL6 promotes the polyubiquitination and activation of a previously uncharacterized substrate, RPL4, which requires JNK2-mediated phosphorylation at Ser295. Activated RPL4 upregulates YY1, increases PD-L1, and then activates the AKT/mTOR pathway, leading to extracellular matrix production and liver fibrosis. Furthermore, the knockdown of RPL4 enhances the efficacy of anti-PD-L1 immunotherapy in FBXL6-driven liver fibrosis in mice, which provides a promising therapeutic strategy for liver fibrosis treatment.