Saffron compound shows promise against fatty liver disease
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Compound screenings identify Crocin II as a potential drug targeting ANGPTL8.
view moreCredit: Compound screenings identify Crocin II as a potential drug targeting ANGPTL8.
A research team has identified Crocin II, a natural compound derived from saffron, as a promising therapeutic candidate for metabolic dysfunction-associated steatotic liver disease (MASLD). The study shows that Crocin II directly targets angiopoietin-like protein 8 (ANGPTL8), a liver-derived regulator of lipid metabolism and inflammation, and promotes its degradation through the autophagosome–lysosome pathway. By reducing ANGPTL8 protein levels, Crocin II alleviated liver fat accumulation, improved lipid profiles, reduced inflammatory changes, and enhanced glucose and insulin responses in experimental models.
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
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.
Journal
Targetome
Subject of Research
Not applicable
Article Title
Crocin II alleviates metabolic dysfunction-associated steatotic liver disease by enhancing autophagic degradation of ANGPTL8
Reinventing perilla: Genome editing boosts a traditional herb’s potential
Disrupting a single enzyme gene in red perilla reshaped its metabolism, producing green plants enriched in health-promoting molecules
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Genome-edited perilla plants (left) showing a striking color change from red to green and enhanced accumulation of the health-promoting flavonoid luteolin.
view moreCredit: Matsushita et al. / Hiroshima Prefectural Technology Research Institute
From traffic lights to fashion trends, changing from red to green can signal much more than a shift in color.
Now, Hiroshima University researchers have shown that the same is true for perilla. Using genome editing, they transformed red perilla into a green look-alike and simultaneously restructured the plant’s chemistry to boost levels of compounds prized for their potential health benefits. The findings point to a new strategy for developing high-value crops for the food and pharmaceutical industries.
The study was published in Frontiers in Plant Science on June 15.
Perilla, a member of the mint family, is cultivated throughout Asia and is known by many names, including shiso in Japan, kkaennip in Korea and tía tô in Vietnam. The plant is broadly classified into red and green varieties based on leaf color, a trait that strongly influences its culinary uses, market value and consumer appeal. In Japan, red perilla is valued for imparting a distinctive color and flavor to pickled plums, whereas green perilla is commonly consumed fresh for its aroma and taste.
Whilst best known as a culinary herb, perilla also carries a range of health-benefiting properties.
“Perilla contains more than 400 bioactive compounds, including anthocyanins, luteolin, rosmarinic acid and perillaldehyde, which have been associated with antioxidant, anti-inflammatory, antibacterial and other health-promoting effects,” said Hidemasa Bono, professor at Hiroshima University’s Graduate School of Integrated Sciences for Life and a corresponding author of the study.
The genetic mechanisms controlling the production and balance of these compounds, however, have remained largely unknown.
Seeking an answer, the researchers turned to CRISPR-Cas9, a genome-editing technology that allows scientists to precisely modify DNA. On red perilla, the team disabled a gene called flavanone 3-hydroxylase (F3H), which encodes an enzyme that acts as a key branching point in the flavonoid biosynthetic pathway.
The result was immediately visible.
“Plants edited at the F3H gene lost their characteristic red pigmentation and developed green leaves that were virtually indistinguishable in appearance from conventional green perilla varieties,” Bono said.
Chemical analyses revealed that the color change reflected a major metabolic shift. The edited plants produced far lower amounts of anthocyanins, the pigments responsible for red coloration, while accumulating substantially higher levels of flavones, a class of plant compounds associated with multiple health benefits. In particular, concentrations of luteolin, a flavone known for its antioxidant and anti-inflammatory properties, increased approximately sixfold compared with unedited plants.
The researchers also detected elevated levels of rosmarinic acid, another bioactive metabolite linked to potential health benefits, suggesting that editing F3H influences not only flavonoid production but broader phenylpropanoid metabolism.
Importantly, the team generated stable edited lines that no longer contained foreign DNA from the genome-editing process. This demonstrates the feasibility of producing non-transgenic perilla varieties with tailored metabolic profiles.
“By modifying a single enzyme gene in red perilla, we have successfully changed the plant’s metabolism to increase its health-promoting compounds,” Bono said. “Genome editing makes it possible to develop high-performance perilla with enhanced value for food and pharmaceutical applications.”
The team plans to use the newly developed lines to further investigate the complex biological functions of perilla and deepen understanding of how its diverse metabolites are regulated.
“We hope to translate these findings into the development of high-value functional foods enriched with beneficial compounds and to explore the use of perilla as a new source of naturally derived pharmaceutical materials,” Bono said.
The research team includes Shuji Matsushita, Suguru Chokyuu, Masaki Kurao, Ayane Fujita, and Junko Kimura at the Hiroshima Prefectural Technology Research Institute; Michiharu Nakano, Keita Tamura, and Hidemasa Bono at Hiroshima University; and Chinatsu Nagata and Takeshi Ishikawa at Mishima Foods Co., Ltd.
The study was supported by the Hiroshima Prefectural Government “Hiroshima Health and Medical-Related Industry Creation Support Project,” and the Center of Innovation for Bio-Digital Transformation (BioDX), an open innovation platform for industry-academia co-creation of JST (COI-NEXT, JPMJPF2010).
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About Hiroshima University
Since its foundation in 1949, Hiroshima University has striven to become one of the most prominent and comprehensive universities in Japan for the promotion and development of scholarship and education. Consisting of 12 schools for undergraduate level and 5 graduate schools, ranging from natural sciences to humanities and social sciences, the university has grown into one of the most distinguished comprehensive research universities in Japan. English website: https://www.hiroshima-u.ac.jp/en
Journal
Frontiers in Plant Science
Article Title
CRISPR-Cas9 disruption of flavanone 3-hydroxylase produces a green phenotype and alters flavone metabolites in allotetraploid perilla
Article Publication Date
15-Jun-2026
