Indian lychee honey mitigates hepatic lipotoxicity via FAM134B-mediated reticulo-mito-phagy in MASLD

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) involves hepatic lipid accumulation and disrupted organelle homeostasis. Indian lychee honey was investigated for its potential to alleviate this lipotoxicity. Purpose This study aimed to elucidate the therapeutic mechanisms of lychee honey, focusing on organelle crosstalk and autophagic processes in MASLD. Study design The study combined in vivo and in vitro models. A high-fat diet (HFD)-induced MASLD mouse model was used for primary assessment. Complementary in vitro experiments employed pharmacological agents- and/or siRNA-mediated induction or inhibition of endoplasmic reticulum (ER)-phagy and fatty acid oxidation (FAO) to confirm the mechanistic pathways. Methods C57BL/6 mice were fed an HFD to induce MASLD and subsequently treated with lychee honey. In vitro models involved treating cells with pharmacological inducers of ER stress and inhibitors of FAO and ER-phagy alongside lychee honey treatment. Analyses included assessment of lipid droplet size, measurement of mitochondria ER contact sites (MERCSs) proximity, evaluation of oxidative stress and inflammatory markers, and confirmation of reticulo-mito-phagy activation. Results Lychee honey treatment significantly reduced hepatic lipid content by enhancing FAO. This restored the physical and functional integrity of MERCSs, improving inter-organelle (ER and mitochondria) communication. Consequently, lychee honey activated coordinated reticulo-mito-phagy, clearing damaged mitochondria (mitoplasts), which mitigated ER stress, oxidative stress, and inflammation. In vitro studies confirmed that lychee honey’s benefits are directly dependent on FAO activation. Conclusion Lychee honey alleviates MASLD by enhancing fatty acid oxidation, restoring MERCSs, and promoting FAM134B-mediated reticulo-mito-phagy. These effects mitigate lipotoxicity and maintain organelle homeostasis, supporting its potential as a nutraceutical intervention for metabolic disorders.