Metabolic dysfunction‑associated steatotic liver disease (MASLD) affects over one‑quarter of adults worldwide and is a rapidly rising cause of cirrhosis, liver failure, and transplantation. Current therapies show suboptimal efficacy, and safe, targeted treatments remain urgently needed. ANGPTL8 has emerged as a promising therapeutic target due to its central roles in hepatic lipid accumulation and inflammation, but existing ANGPTL8‑targeting approaches (antisense oligonucleotides, monoclonal antibodies) face limitations in stability, delivery, and cost.
A research team led by Prof. Chang Liu, Prof. Wenxiang Zhang, and Prof. Siyu Chen from China Pharmaceutical University has identified crocin II, a major bioactive ingredient of saffron, as a potent, natural ANGPTL8 degrader. Using molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and surface plasmon resonance (SPR), the team confirmed that crocin II binds ANGPTL8 directly and strongly (
KD = 1.276 μM).
Mechanistically, crocin II drives selective autophagic degradation of ANGPTL8 through the autophagosome‑lysosome pathway, independent of the proteasome. It also binds the autophagy adaptor P62, enhancing ANGPTL8‑P62 interaction and efficient targeting to autophagosomes. This reduces ANGPTL8 protein half‑life and downregulates lipogenic genes (Fasn, Dgat1, Cidea) while restoring lipolysis (Atgl).
In vitro, crocin II dose‑dependently alleviated free fatty acid‑induced lipid overload in mouse primary hepatocytes. These lipid‑lowering effects were completely dependent on ANGPTL8, validated in knockout and overexpression assays.
In high‑fat diet (HFD)‑induced MASLD mice, crocin II:
Reduced body weight, liver weight, and epididymal fat mass;
Improved glucose intolerance and insulin resistance;
Lowered serum triglycerides, total cholesterol, LDL‑cholesterol, and liver enzymes ALT/AST;
Markedly reduced hepatic steatosis and macrophage infiltration;
Reprogrammed the hepatic lipidome toward a healthy profile;
Showed no organ toxicity in the heart, kidneys, or spleen.
Notably, crocin II is derived from a widely used medicinal and edible plant, supporting high safety and translational potential. Unlike biologicals, it acts as a natural PROTAC‑like degrader with oral potential and low cost.
These findings establish ANGPTL8 as a druggable target for MASLD and validate crocin II as a promising lead candidate for further clinical development.
This work entitled “
Crocin II alleviates metabolic dysfunction‑associated steatotic liver disease by enhancing autophagic degradation of ANGPTL8” was published online April 3, 2026, in
Targetome.
DOI：10.48130/targetome-0026-0018