Agriophyllum squarrosum oligosaccharides ameliorate inflammation and lipid accumulation in T2DM-induced MASLD via miR-155-regulated PPARγ signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Agriophyllum squarrosum (L.) Moq., is a traditional medicinal herb first recorded in the "Four Medical Tantras" during the 8th century AD. It is commonly employed in Mongolian medicine for various therapeutic diseases, including the dispelling epidemics, heat clearance, detoxification, and diuresis. This herb is known to inhibit "He Yi," regulate "Ba Da Gan," and is utilized in the treatment of "Xi He Ri Xi Jing Bing" which corresponds to modern diabetes and xiaoke in traditional Chinese medicine. Agriophyllum squarrosum oligosaccharides (AOS) are recognized as major bioactive constituents, however, the molecular mechanisms underlying their therapeutic effects on type 2 diabetes mellitus (T2DM)-related metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear.

AIM OF THE STUDY: This study investigates the therapeutic effects of AOS in T2DM-MASLD and explores the underlying mechanisms involving miR-155-mediated signaling pathways.

MATERIALS AND METHODS: In vivo, db/db mice were treated with AOS, and hepatic lipid accumulation and insulin resistance were evaluated using biochemical and histological analyses. Hepatic expression of miR-155 and associated signaling proteins was observed by qRT-PCR, Western blotting, and immunohistochemistry. Exosomes derived from ATMs of db/db mice were co-cultured with AML-12 hepatocytes to investigate the role of exosomal miR-155 in MASLD progression. In vitro, inflammatory cytokine production and miR-155 expression were quantified using ELISA and qRT-PCR, while exosomal miR-155 secretion was evaluated in glucolipid-induced cellular injury models.

RESULTS: AOS treatment reduced hepatic steatosis and improved insulin resistance in db/db mice. AOS was associated with decreased hepatic miR-155 expression. Exosomal miR-155 derived from ATMs aggravated hepatocyte injury in the co-culture system, accompanied by increased expression of SREBP1c, NLRP3, and NF-κB p65. In vitro, AOS inhibited exosomal miR-155 secretion and downregulated the expression of SREBP1c, P2X7R, NF-κB p65, and inhibitor of IκBα, thus attenuating glucolipid metabolism-associated inflammatory responses and lipid dysregulation.

CONCLUSION: AOS ameliorates inflammation, hepatic lipid accumulation, and insulin resistance in T2DM-associated MASLD, possibly via suppression of miR-155 and modulation of downstream inflammatory and lipogenic signaling pathways. These results identify AOS as a promising therapeutic candidate for treating T2DM-associated MASLD.