Crocin II Targets ANGPTL8 to Reduce MASLD Progression in Preclinical Study

A study published in Targetome on 03 April 2026 by researchers from China Pharmaceutical University shows that Crocin II, a natural compound from saffron, binds to ANGPTL8 and accelerates its degradation, reducing liver steatosis and metabolic dysfunction in mice. The findings support Crocin II as…

The Challenge of MASLD and the ANGPTL8 Target

Metabolic dysfunction-associated steatotic liver disease, or MASLD, has become one of the most widespread chronic liver conditions globally. It now affects more than one-quarter of adults worldwide. The disease is closely linked to several serious health issues, including obesity, dyslipidemia, type 2 diabetes, cardiovascular disease, chronic kidney disease, and liver cancer. Researchers have explored many therapeutic targets, including pathways that involve bile acid signaling and lipid metabolism. However, current drug development remains limited by insufficient efficacy, safety concerns, or challenges in translating findings from the lab to the clinic.

Angiopoietin-like protein 8, known as ANGPTL8, has emerged as a valuable target for MASLD treatment. This protein participates in lipid regulation, inflammatory signaling, and the metabolic rhythm of the liver. Existing approaches to target ANGPTL8 include antisense oligonucleotides and monoclonal antibodies. While these have shown some potential, they face significant challenges such as delivery limitations, high cost, instability, and possible side effects. These drawbacks highlight the need for small-molecule or natural-compound alternatives that can target ANGPTL8 more effectively and safely.

Study Design: Screening Natural Compounds for ANGPTL8 Binding

A research team led by Chang Liu, Wenxiang Zhang, and Siyu Chen from China Pharmaceutical University conducted a study to identify natural compounds capable of targeting ANGPTL8. Their work was published in the journal Targetome on 03 April 2026, with the DOI 10.48130/targetome-0026-0012. The researchers built a library of saffron-derived small molecules containing 70 chemical monomers. They then performed molecular docking simulations against both human and mouse ANGPTL8 proteins.

From this screening, two compounds stood out: Crocin I and Crocin II. Both showed strong predicted binding affinity to ANGPTL8. Crocin II emerged as the more powerful candidate of the two. The team then verified the interaction using several complementary laboratory assays. A cellular thermal shift assay and drug affinity responsive target stability analysis confirmed that Crocin II interacts with ANGPTL8 and promotes its degradation. Surface plasmon resonance measurements showed that Crocin II had stronger binding affinity than Crocin I. Molecular dynamics simulations further indicated that the Crocin II-ANGPTL8 complex remained structurally stable over time.

How Crocin II Works in Cells and Mice

The researchers next examined how Crocin II reduces ANGPTL8 levels in mouse primary hepatocytes. They found that Crocin II lowered both intracellular and secreted ANGPTL8 in a dose-dependent and time-dependent manner, without causing significant cellular toxicity. Protein stability tests showed that Crocin II shortened the half-life of the ANGPTL8 protein. Pathway inhibition experiments demonstrated that this degradation was mainly mediated by the autophagosome-lysosome system. Further evidence included increased levels of LC3B-II, decreased levels of P62, transmission electron microscopy images, and mCherry-eGFP-LC3 fluorescence imaging, all of which supported that Crocin II induces autophagic activation.

Functional experiments revealed that ANGPTL8 promotes lipid accumulation by increasing the expression of lipogenic genes such as Fasn, Dgat1, and Cidea, while suppressing lipolytic genes such as Atgl. Crocin II reversed these effects and reduced free fatty acid-induced lipid accumulation in hepatocytes. In cells that were deficient in Angptl8, Crocin II produced little additional lipid-lowering effect. When Angptl8 was overexpressed, Crocin II's protective action was weakened. These findings confirm that ANGPTL8 mediates the metabolic benefit of Crocin II.

The study then moved to animal experiments. In mice fed a high-fat diet, Crocin II reduced body weight gain. It improved glucose tolerance and insulin sensitivity. It lowered serum triglycerides, total cholesterol, low-density lipoprotein cholesterol, and the LDL-C to HDL-C ratio. Liver injury markers also decreased. Histological staining showed less hepatic lipid deposition and less macrophage infiltration in the liver. Liver triglyceride and cholesterol levels were markedly reduced. Untargeted lipidomics analysis revealed that Crocin II reshaped hepatic lipid metabolism, reducing many types of triglycerides, diglycerides, cholesteryl esters, and fatty acyl species. Importantly, no overt toxic effects were observed in the kidney, heart, or spleen of the treated mice.

Implications for Future Treatment

The study reveals a natural-compound-based mechanism for targeting ANGPTL8 in MASLD. By promoting autophagic degradation of ANGPTL8, Crocin II reduced hepatic steatosis, improved systemic metabolic dysfunction, and showed favorable preliminary safety in animal experiments. The findings support Crocin II as a promising lead compound for future MASLD drug development and reinforce ANGPTL8 as an important therapeutic target for metabolic disease.

This work was financially supported by several grants. These include the National Key R&D Program of China under Grant No. 2022YFA0807200, the National Natural Science Foundation of China under Grant No. 32471201, the Natural Science Foundation of Jiangsu Province under Grant No. BK20220151, and the Project of State Key Laboratory of Natural Medicines at China Pharmaceutical University under No. SKLNMZZ2024JS34. Additional funding came from the Open Research Fund of Yunnan Characteristic Plant Extraction Laboratory under Grant No. YKKF2024018, the Priority Academic Program Development of Jiangsu Higher Education Institutions PAPD , and The National Innovation and Entrepreneurship Training Program for Undergraduates.

Targetome is an open access journal that publishes peer-reviewed original research articles, reviews, breakthrough methods, and perspectives. The journal focuses on advancing the understanding, identification, and validation of molecular targets for new drug development.