MASLD has become one of the most common chronic liver diseases worldwide, affecting more than one-quarter of adults and closely linked to obesity, dyslipidemia, type 2 diabetes, cardiovascular disease, chronic kidney disease, and liver cancer. Although multiple therapeutic targets have been explored, including pathways involved in bile acid signaling and lipid metabolism, current drug development remains limited by insufficient efficacy, safety concerns, or translational barriers. ANGPTL8 has emerged as a valuable target because it participates in lipid regulation, inflammatory signaling, and hepatic metabolic rhythm. Existing ANGPTL8-targeted approaches, such as antisense oligonucleotides and monoclonal antibodies, have shown potential but face challenges including delivery limitations, high cost, instability, and possible side effects, highlighting the need for small-molecule or natural-compound alternatives.
A study (DOI: 10.48130/targetome-0026-0012) published in Targetome on 03 April 2026 by Chang Liu, Wenxiang Zhang & Siyu Chen's team, China Pharmaceutical University, reports that Crocin II binds ANGPTL8 and reduces MASLD progression by accelerating ANGPTL8 protein degradation.
To identify natural compounds capable of targeting ANGPTL8, the researchers built a saffron-derived small-molecule library containing 70 chemical monomers and performed molecular docking against human and mouse ANGPTL8. Crocin I and Crocin II showed strong predicted binding affinity, with Crocin II emerging as the more powerful candidate. The team then verified this interaction using several complementary assays. Cellular thermal shift assay and drug affinity responsive target stability analysis confirmed that Crocin II interacts with ANGPTL8 and promotes its degradation, while surface plasmon resonance 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. The researchers next examined how Crocin II reduced ANGPTL8 levels in mouse primary hepatocytes. Crocin II lowered both intracellular and secreted ANGPTL8 in a dose- and time-dependent manner without significant cellular toxicity. Protein stability tests showed that Crocin II shortened the half-life of ANGPTL8, while pathway inhibition experiments demonstrated that this degradation was mainly mediated by the autophagosome–lysosome system. Increased LC3B-II, decreased P62, transmission electron microscopy, and mCherry–eGFP–LC3 fluorescence imaging supported Crocin II-induced autophagic activation. Functional experiments showed that ANGPTL8 promoted lipid accumulation by increasing lipogenic genes such as Fasn, Dgat1, and Cidea and suppressing lipolytic genes such as Atgl. Crocin II reversed these effects and reduced free fatty acid-induced lipid accumulation in hepatocytes. In Angptl8-deficient cells, Crocin II produced little additional lipid-lowering effect, while Angptl8 overexpression weakened Crocin II's protective action, confirming that ANGPTL8 mediates the compound's metabolic benefit. In mice fed a high-fat diet, Crocin II reduced body weight gain, improved glucose tolerance and insulin sensitivity, lowered serum triglycerides, total cholesterol, low-density lipoprotein cholesterol, and the LDL-C/HDL-C ratio, and decreased liver injury markers. Histological staining showed less hepatic lipid deposition and macrophage infiltration, while liver triglyceride and cholesterol levels were markedly reduced. Untargeted lipidomics revealed that Crocin II reshaped hepatic lipid metabolism, reducing many triglyceride, diglyceride, cholesteryl ester, and fatty acyl species. Importantly, no overt toxic effects were observed in the kidney, heart, or spleen.
Together, 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.
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References
DOI
10.48130/targetome-0026-0012
Original Source URL
https://doi.org/10.48130/targetome-0026-0012
Funding information
This work was financially supported by grants from the National Key R&D Program of China (Grant No. 2022YFA0807200), the National Natural Science Foundation of China (Grant No. 32471201), the Natural Science Foundation of Jiangsu Province (Grant No. BK20220151), the Project of State Key Laboratory of Natural Medicines, China Pharmaceutical University (no. SKLNMZZ2024JS34), the Open Research Fund of Yunnan Characteristic Plant Extraction Laboratory (Grant No. YKKF2024018), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and The National Innovation and Entrepreneurship Training Program for Undergraduates.
About Targetome
Targetome refers to the complete collection of molecular targets (e.g., proteins, RNA or DNA) that interact with and mediate the effect of a specific biomolecule, such as a drug, toxin, metabolites, transcription factor or microRNA, within a biological system. Targetome is an open access journal publishing rigorously peer-reviewed original research articles, reviews, break-through methods, and perspectives that advance our understanding, identification and validation of molecular targets for new drug development.