Targeting RPL4 improves the therapeutic efficacy of PD-L1 blockade in liver fibrosis
- 1Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
- 2Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
Abstract
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.
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BibTeX
@article{zhang2026targeting,
title = {{Targeting RPL4 improves the therapeutic efficacy of PD-L1 blockade in liver fibrosis}},
author = {Jie Zhang and Chun-Ming Li and Lei Fang and Xiao-Tong Lin and Ke Min and Di Wu and De-Hong Tan and Zhi-Yu Chen and Lei-Da Zhang and Chuan-Ming Xie},
journal = {Cell Reports Medicine},
year = {2026},
month = sep,
doi = {10.1016/j.xcrm.2026.103056},
url = {https://doi.org/10.1016/j.xcrm.2026.103056},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Targeting RPL4 improves the therapeutic efficacy of PD-L1 blockade in liver fibrosis
AU - Jie Zhang
AU - Chun-Ming Li
AU - Lei Fang
AU - Xiao-Tong Lin
AU - Ke Min
AU - Di Wu
AU - De-Hong Tan
AU - Zhi-Yu Chen
AU - Lei-Da Zhang
AU - Chuan-Ming Xie
PY - 2026
DA - 2026/09/22
JO - Cell Reports Medicine
DO - 10.1016/j.xcrm.2026.103056
UR - https://doi.org/10.1016/j.xcrm.2026.103056
AB - 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.
SN - 2666-3791
ER -