A natural small molecule alleviates liver fibrosis by targeting apolipoprotein L2
Liver fibrosis is an urgent clinical problem without effective treatment. Herein, we conduct a high-content screening on a natural “privileged” diterpenoid library to identify a potent anti-liver fibrosis lead DP. Leveraging photoaffinity labeling approach, apolipoprotein L2 (APOL2), an ER-rich protein, is identified as the direct target of DP. APOL2 is mainly expressed in activated hepatic stellate cells (HSCs) and could activate HSCs to synthesize ECM proteins. It can be induced by TGF-b1 and be antagonized by DP. Mechanistically, upon TGF-b1 stimulation, APOL2 binds ER Ca2+ pump SERCA2 to trigger ER stress, elevating its downstream PERK-HES1 axis to promote liver fibrosis, mildly dependent on the canonical TGF-b/Smad signaling. As a result, ablation of APOL2 significantly alleviates TGF-b1-stimulated HSCs activation, and abolishes anti-fibrosis effect of DP. Our findings not only define APOL2 as a novel therapeutic target for liver fibrosis, but also highlight DP as a promising lead for treatment of this symptom. Overall design: LX-2 cells mRNA profiles of treatment with DMSO, TGF-b1, and TGF-b1 + 10 µM DP for 48 h.