Hexavalent phospholipids ameliorate alcoholic liver disease by modulating lipid metabolism via the p38 MAPK/CD36 axis

Abstract

Abstract: Objective To investigate the hepatoprotective effects of HexaV in ALD and elucidate its underlying molecular mechanisms, with particular focus on its regulatory pathways in lipid metabolic dysregulation. Methods 30 male SPF-grade C57BL/6 mice were randomly divided into three groups: the control group (normal saline, 5 g/kg, once daily for 8 weeks), the ALD model group (32.5% absolute ethanol, 5 g/kg, once daily for 8 weeks), and the ALD + HexaV group (32.5% absolute ethanol (5 g/kg) + HexaV (0.8 mg/g), once daily for 8 weeks). Mouse serum and liver tissues were collected, and biochemical indicators in mouse serum were detected. Pathological changes in mouse liver tissues were observed through HE and Oil Red O staining. Transcriptome sequencing, q-PCR and Western Blot were performed on mouse liver tissues to detect the mRNA and protein expression of related genes. Results Compared to the control group, alcohol treatment increased plasma ALT (U/L) levels (430.90±150.56 vs. 228.80 ±115.87, t=2.450, P=0.036). After HexaV treatment, plasma ALT (U/L) (ALD+HexaV group vs. control group: 34.15±19.79 vs. 228.80±115.87, t=4.766, P=0.001; ALD+HexaV group vs. ALD group: 34.15±19.79 vs. 430.90±150.56, t=7.470,P<0.001) and AST (U/L) (ALD+HexaV group vs. control group: 246.00±95.40 vs. 690.80±148.28, t=6.667, P<0.001; ALD+HexaV group vs. ALD group: 246.00±95.40 vs. 639.40±160.57, t=5.764, P<0.001) levels were reduced compared to both the control group and the ALD model group. Compared to the control group, the ALD model group showed a significant increase in TC (mmol/L) content (3.61±0.20 vs. 1.80±0.34, t=8.529,P<0.001). In the ALD+HexaV group, plasma TC (mmol/L) (ALD+HexaV group vs. ALD group: 3.27±0.12 vs. 3.61±0.20, t=2.894, P=0.034) and TG (mmol/L) (ALD+HexaV group vs. ALD group: 0.53±0.03 vs. 0.67±0.06, t=3.575, P=0.011) levels were significantly reduced compared to the ALD group. Histological assessment (H&E and Oil Red O staining) confirmed HexaV-mediated attenuation of liver injury and steatosis in ALD mice. RNA-seq analysis identified 66 consensus DEGs, with 51 showing reversal of ALD-induced upregulation and 15 exhibiting rescure of ALD-suppressed expression following HexaV treatment. KEGG pathway analysis identified significant enrichment of DEGs in lipid metabolic and pro-inflammatory cascades. GSEA confirmed marked activation of atherogenic pathways (Fat digestion and absorption Lipid and atherosclerosis, PPAR signaling pathway) in ALD mice, with complete reversal following HexaV intervention. Ranscriptomic enrichment analysis revealed significant involvement of the MAPK signaling pathway. Western Blot confirmed p38 hyperphosphorylation in ALD mice, which was attenuated by HexaV treatment. Conclusion Our study demonstrates that HexaV attenuates alcoholic steatosis through selective inhibition of the p38 MAPK-CD36 axis, revealing both a druggable pathway in ALD pathogenesis and a clinically actionable therapeutic strategy.

Key words: Hexavitamin soya Lecithin, Alcohol-associated liver disease, Lipid metabolism, CD36, p38 MAPK signaling pathway

GENG Wen-qian, WANG Yang, LI Jia-xi, YUAN Xiao-xue, YANG Song. Hexavalent phospholipids ameliorate alcoholic liver disease by modulating lipid metabolism via the p38 MAPK/CD36 axis[J]. Chinese Hepatolgy, 2026, 31(2): 271-278.

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