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Xuan Zhang

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Aug 2026

Guaijaverin, a guava-derived flavonoid, attenuates high-fat diet-induced MASLD via regulating the gut microbiota-SCFA-ferroptosis axis.

Guaijaverin (GUA), a guava-derived bioactive flavonoid, is a promising candidate for the development of functional foods targeting metabolic disorders. This study investigated the protective effects and underlying mechanisms of GUA against high-fat diet (HFD)-induced metabolic dysfunction-associated steatotic liver disease (MASLD), with particular emphasis on the gut-liver axis. Using an HFD-fed mouse model and free fatty acid (FFA)-stimulated AML12 hepatocytes, we integrated hepatic phenotypic evaluation, 16S rRNA sequencing, short-chain fatty acid (SCFA) quantification, antibiotic-mediated microbiota depletion, sodium butyrate supplementation, RSL3 rescue experiments, and hepatic transcriptomic analysis. GUA markedly alleviated hepatic steatosis, improved serum and hepatic lipid accumulation, and reduced liver injury. GUA also restored intestinal barrier integrity, reshaped gut microbiota composition, enriched SCFA-associated bacteria, and increased fecal SCFA levels. Antibiotic depletion attenuated the hepatoprotective effects of GUA, whereas butyrate supplementation partially restored these effects, supporting the involvement of gut microbiota-derived butyrate in GUA-mediated liver protection. Liver transcriptomic analysis further identified glutathione metabolism as a major pathway activated by GUA. Consistently, GUA restored redox homeostasis, reduced iron overload and lipid peroxidation, and maintained the GPX4-mediated anti-ferroptotic defense axis. These effects were weakened by microbiota depletion and partially rescued by butyrate supplementation. In AML12 hepatocytes, pharmacological induction of ferroptosis with RSL3 partially abolished the protective effects of GUA or sodium butyrate, further supporting ferroptosis inhibition as a functional downstream mechanism. Collectively, these findings indicated that GUA ameliorated HFD-induced MASLD, at least in part, through coordinated modulation of the gut microbiota-SCFA-ferroptosis axis, highlighting its potential as a guava-derived functional food ingredient for metabolic liver health.

Xuan Zhang, Xu Han, Jia-Jun Hang et al. · Food & Function · 0 citations

Open access Aug 2026

Targeting ACOT1-SLC25A5 Axis attenuates LPS-induced acute liver injury by inhibiting ferroptosis and inflammatory responses.

Sepsis associated acute liver injury is a major contributor to multiple organ dysfunction and mortality in critically ill patients. ACOT1 has emerged as a promising therapeutic target, demonstrated to inhibit disseminated intravascular coagulation through its anti-ferroptosis activity. However, its specific function and mechanistic role in the context of during endotoxemia-induced liver injury have not been elucidated. This study demonstrates that ferroptosis was markedly activated in both lipopolysaccharide (LPS)-stimulated AML12 hepatocytes and LPS-induced acute liver injury mouse models. RNA sequencing and bioinformatics analyses identified ACOT1 as the most significantly downregulated genes following LPS stimulation. Functionally, ACOT1 overexpression upregulated GPX4 and SLC7A11 expression, reduced mitochondrial ROS and Fe2+ accumulation, which ultimately attenuated LPS-induced hepatocyte ferroptosis. Mechanistically, ACOT1 overexpression activated PPARγ, thus suppressing NF-κB pathway activation and inflammatory responses thereafter. IP-MS and immunofluorescence staining confirmed that SLC25A5 interacts with ACOT1 and functions as a molecular partner in regulating hepatocyte ferroptosis by reducing mitochondrial ROS and Fe2+ levels. Protein interaction analysis between ACOT1 and SLC25A5 showed a Rosetta score of -271.16 kcal/mol, indicating strong binding affinity. Collectively, our results identified ACOT1 as a novel inhibitor of ferroptosis in LPS-induced acute liver injury. ACOT1 exerts protective effects by modulating the PPARγ/NF-κB signaling axis and cooperating with SLC25A5 to regulate oxidative stress-driven ferroptosis. These results highlight ACOT1 as a potential regulator for inflammatory liver injury.

Chengzhu Xu, Shun Wang, Xiyang Wang et al. · International Immunopharmaco... · 0 citations