Role of LncSNHG5 in MAFLD: Mechanisms of Arid1a K391 lactylation and lipid accumulation

Abstract

Introduction: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic liver condition marked by abnormal lipid metabolism.

Objectives: Small nucleolar RNA host gene 5 (SNHG5) is involved in the regulation of cell proliferation and apoptosis and was previously identified as a profibrotic factor in liver fibrosis. However, its role in MAFLD remains unclear. This study aimed to elucidate the contribution of SNHG5 to MAFLD progression.

Methods and results: SNHG5 expression was markedly elevated during MAFLD progression, whereas SNHG5 inhibition suppressed lipid accumulation. Transcriptomic sequencing of primary hepatocytes overexpressing SNHG5 demonstrated significant downregulation of monocarboxylate transporter 1 (MCT1), a key lactate transporter. Integrated lactyl-proteomic and proteomic analyses further revealed that SNHG5 overexpression promoted lactylation of the non-histone protein AT-rich interaction domain 1A (Arid1a) at K391, thereby driving excessive lipid accumulation. Acyltransferase assays indicated that both P300 and HBO1 participated in SNHG5-mediated Arid1a lactylation. In vivo, hepatocyte-specific SNHG5 knockout markedly attenuated hepatic lipid accumulation and MAFLD progression, whereas simultaneous hepatocyte-specific deletion of SNHG5 and MCT1 restored lipid accumulation compared with SNHG5-deficient mice.

Conclusion: SNHG5 promotes lipid accumulation and MAFLD progression through induction of MCT1-mediated Arid1a K391 lactylation.

Keywords

HBO1 / lactylation / LncSNHG5 / MAFLD / P300

References

[1] Zha X, Gao Z, Li M, Xia X, Mao Z, Wang S. Insight into the regulatory mechanism of m6A modification: from MAFLD to hepatocellular carcinoma. Biomed Pharmacother. 2024; 177:116966.

[2] Wang Y-F, Zhang W-L, Li Z-X, et al. METTL14 downregulation drives S100A4+ monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression. Signal Transduct Target Ther. 2024; 9(1): 91.

[3] Phoolchund AGS, Khakoo SI. MASLD and the development of HCC: pathogenesis and therapeutic challenges. Cancers. 2024; 16(2):259.

[4] Zhao Y, Zhou Y, Wang D, et al. Mitochondrial dysfunction in metabolic dysfunction fatty liver disease (MAFLD). Int J Mol Sci. 2023; 24(24):17514.

[5] Song BG, Choi SC, Goh MJ, et al. Metabolic dysfunction-associated fatty liver disease and the risk of hepatocellular carcinoma. JHEP Rep. 2023; 5(9):100810.

[6] Argenziano ME, Kim MN, Montori M, et al. Epidemiology, pathophysiology and clinical aspects of hepatocellular carcinoma in MAFLD patients. Hepatol Int. 2024; 18: 922-940.

[7] Soltanieh SK, Khastar S, Kaur I, et al. Long non-coding RNAs in non-alcoholic fatty liver disease; friends or foes? Cell Biochem Biophys. 2024; 83(1): 279-294.

[8] Damas ND, Marcatti M, Côme C, et al. SNHG5 promotes colorectal cancer cell survival by counteracting STAU1-mediated mRNA destabilization. Nature Commun. 2016; 7(1):13875.

[9] Zheng J, Guo H, Qin Y, et al. SNHG5/miR-582-5p/RUNX3 feedback loop regulates osteogenic differentiation and apoptosis of bone marrow mesenchymal stem cells. J Cell Physiol. 2020; 239(12):29527.

[10] Yang Y, Xi L, Ma Y, et al. The lncRNA small nucleolar RNA host gene 5 regulates trophoblast cell proliferation, invasion, and migration via modulating miR-26a-5p/N-cadherin axis. J Cell Biochem. 2018; 120(3): 3173-3184.

[11] Zhang R, Zhan Y, Lang Z, Li Y, Zhang W, Zheng J. LncRNA-SNHG5 mediates activation of hepatic stellate cells by regulating NF2 and Hippo pathway. Commun Biol. 2024; 7(1): 266.

[12] Li Y, Guo D, Zhao Y, et al. Long non-coding RNA SNHG5 promotes human hepatocellular carcinoma progression by regulating miR-26a-5p/GSK3β signal pathway. Cell Death Disease. 2018; 9(9): 888.

[13] Hao J, Liu Y, Guo F, et al. Lnc-SNHG5 promoted hepatocellular carcinoma progression through the RPS3‒NFκB pathway. Int J Gen Med. 2023; 16: 5651-5664.

[14] Wang J, Wang Z, Wang Q, Li X, Guo Y. Ubiquitous protein lactylation in health and diseases. Cell Mol Biol Lett. 2024; 29(1): 23.

[15] Chen S, Xu Y, Zhuo W, Zhang L. The emerging role of lactate in tumor microenvironment and its clinical relevance. Cancer Lett. 2024; 590:216837.

[16] Lin J, Ren J. Lactate-induced lactylation and cardiometabolic diseases: from epigenetic regulation to therapeutics. Biochim Biophys Acta Mol Basis Disease. 2024; 1870(6):167247.

[17] Liu JY, Liao W, Chen ZY, et al. PKM2 drives lactate-mediated fibrosis in liver transplantation. Transplantation. 2025; 109(11): e631-e646.

[18] Zhang Y, Peng Q, Zheng J, et al. The function and mechanism of lactate and lactylation in tumor metabolism and microenvironment. Genes Diseases. 2023; 10(5): 2029-2037.

[19] Xu X, Wu X, Jin D, et al. Lactylation: the regulatory code of cellular life activity and a barometer of diseases. Cellular Oncol. 2025; 48(5): 1203-1217.

[20] Singh M, Afonso J, Sharma D, et al. Targeting monocarboxylate transporters (MCTs) in cancer: how close are we to the clinics? Semin Cancer Biol. 2023; 90: 1-14.

[21] Jiao Q, Ren Y, Teng X, et al. Positive feedback between histone H4K16 lactylation and glycolysis promotes MAFLD progression. Hepatol Int. 2025: 10978.

[22] Chen Y, Wu J, Zhai L, et al. Metabolic regulation of homologous recombination repair by MRE11 lactylation. Cell. 2024; 187(2):294-293.211e+223.

[23] Niu Z, Chen C, Wang S, et al. HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription. Nat Commun. 2024; 15(1): 3561.

[24] Liu R, Wu J, Guo H, et al. Post-translational modifications of histones: mechanisms, biological functions, and therapeutic targets. MedComm. 2023; 4(3):e292.

[25] Huang J, Wang X, Li Na, et al. YY1 lactylation aggravates autoimmune uveitis by enhancing microglial functions via inflammatory genes. Adv Sci. 2024; 11(19):e2308031.

[26] Yang K, Fan M, Wang X, et al. Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis. Cell Death Different. 2021; 29(1): 133-146.

[27] Shun Y, Hongyu C, Ting T, et al. Role of lactate and lactate metabolism in liver diseases (review). Int J Mol Med. 2024; 54(1): 59.

[28] Austin M, Linwei W, Jen-Chieh C, et al. Arid1a loss drives nonalcoholic steatohepatitis in mice through epigenetic dysregulation of hepatic lipogenesis and fatty acid oxidation. Hepatology. 2018; 69(5): 1931-1945.

[29] Jiaxing H, Xiaotang W, Na L, et al. YY1 lactylation aggravates autoimmune uveitis by enhancing microglial functions via inflammatory genes. Adv Sci (Weinh). 2024; 11(19):e2308031.

[30] Ziping N, Chen C, Siyu W, et al. HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription. Nat Commun. 2024; 15(1): 3561.

[31] Do A, Zahrawi F, Mehal WZ. Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH). Nat Rev Drug Discov. 2024; 24(3): 171-189.

[32] Chandrasekaran P, Weiskirchen R. The role of SCAP/SREBP as central regulators of lipid metabolism in hepatic steatosis. Int J Mol Sci. 2024; 25(2):1109.

[33] Zhao L, Han T, Li Y, et al. The lncRNA SNHG5/miR-32 axis regulates gastric cancer cell proliferation and migration by targeting KLF4. FASEB J. 2016; 31(3): 893-930.

[34] Li Y, Hu J, Guo D, et al. LncRNA SNHG5 promotes the proliferation and cancer stem cell-like properties of HCC by regulating UPF1 and Wnt-signaling pathway. Cancer Gene Ther. 2022; 29(10): 1373-1383.

[35] Luo X, Li Z, Chen L, et al. Monocarboxylate transporter 1 in the liver modulates high-fat diet-induced obesity and hepatic steatosis in mice. Metabolism. 2023; 143:155537.

[36] Li X, Yang Y, Zhang B, et al. Lactate metabolism in human health and disease. Signal Transduct Target Ther. 2022; 7(1): 305.

[37] Droździk M, Szeląg-Pieniek S, Grzegółkowska J, et al. Monocarboxylate transporter 1 (MCT1) in liver pathology. Int J Mol Sci. 2020; 21(5):1606.

[38] Tao H, Ming-Yu Z, Gao-Liang Z, et al. Focal adhesion kinase promotes aerobic glycolysis in hepatic stellate cells via the cyclin D1/c-Myc/MCT-1 pathway to induce liver fibrosis. Sci Rep. 2025; 15(1): 4552.

[39] Min K, Yenilmez B, Kelly M, et al. Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis. Elife. 2024; 12:RP89136.

[40] Kuo T-L, Hou Y-C, Shan Y-S, Chen L-T, Hung W-C. Arid1a deficiency sensitises pancreatic cancer to fatty acid synthase inhibition. Clin Transl Med. 2025; 15(7):e70394.

[41] Qu YL, Deng CH, Luo Q, et al. Arid1a regulates insulin sensitivity and lipid metabolism. EBioMedicine. 2019; 42: 481-493.

[42] Chang Z, Xu X, Xu Y, et al. Potential effects of functional foods and dietary supplements on metabolic-associated fatty liver disease and the underlying mechanisms: a narrative review with a focus on the modulation of the gut microbiota. J Agric Food Chem. 2025; 73(46): 29247-29280.

Rights & permissions

2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.