The knowledge accumulated over the past two decades has revealed that the natural history of metabolic dysfunction-associated steatotic liver disease (MASLD) and the drivers of the disease severity are not only complex but also exhibit variation among patients. This intricate clinical scenario entails major therapeutic and management implications. In this review, we provide a comprehensive examination of recent advancements in our understanding of MASLD heterogeneity, drawing insights from multiomics and panomics studies.
The discussion herein explores the instrumental role of panomics in MASLD research, elucidating the potential for the identification of molecular subtypes that exhibit divergent survival outcomes or heterogeneous responses to various treatments. Furthermore, we provide insights into the challenges in addressing disease heterogeneity and potential solutions. Finally, the most advanced technological advancements and prospective research directions in the domain of MASLD research are delineated, with the objective of facilitating the implementation of personalized diagnosis and interventions.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a spectrum of pathology involving fatty liver disease that may progress to fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. The prevalence of MASLD and metabolic dysfunction-associated steatohepatitis (MASH) continues to increase, mirroring the rise in global prevalence of related comorbidities such as obesity and type 2 diabetes mellitus. Due to the alarming rise of these comorbidities, a greater proportion of the population is at risk for developing MASLD and MASH. As such, there has been a significant effort to develop effective therapies for MASLD and MASH. Recently, the U.S. Food and Drug Administration approved resmetirom, a selective thyroid hormone receptor-beta agonist, as the first treatment for patients with MASH. In India, the Drug Controller General of India approved saroglitazar, a dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist, for the treatment of MASLD. Currently, we have various drug classes, including liver-specific therapies, in Phase 3 development with even more agents earlier in the pipeline. This review will discuss prospective therapies in later stages of development such as thyroid hormone receptor-beta agonists, PPAR agonists, glucagon-like peptide-1 receptor agonists, fibroblast growth factor 21 agonists, and fatty acid synthase inhibitors.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex multifactorial disease and becoming the leading cause of liver-related morbidity and mortality. MASLD spans from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), that may progress to cirrhosis and hepatocellular carcinoma (HCC). Genetic, metabolic, and environmental factors strongly contribute to the heterogeneity of MASLD. Lifestyle intervention and weight loss represent a viable treatment for MASLD. Moreover, Resmetirom, a thyroid hormone beta receptor agonist, has recently been approved for MASLD treatment. However, most individuals treated did not respond to this therapeutic, suggesting the need for a more tailored approach to treat MASLD. Oligonucleotide-based therapies, namely small-interfering RNA (siRNA) and antisense oligonucleotide (ASO), have been recently developed to tackle MASLD by reducing the expression of genes influencing MASH progression, such as PNPLA3 and HSD17B13. Here, we review the latest progress made in the synthesis and development of oligonucleotide-based agents targeting genetic determinants of MASH.
Rodent model of metabolic dysfunction‐associated fatty liver disease: a systematic review Xiao‐Shan Cui, Hong‐Zheng Li, Liang Li, Cheng‐Zhi Xie, Jia‐Ming Gao, Yuan‐Yuan Chen, Hui‐Yu Zhang, Wei Hao, Jian‐Hua Fu, Hao Guo Journal of Gastroenterology and Hepatology.2025; 40(1): 48. CrossRef
Role of PNPLA3 in Hepatic Stellate Cells and Hepatic Cellular Crosstalk Maria Castanho Martins, Emmanuel Dauda Dixon, Giulia Lupo, Thierry Claudel, Michael Trauner, Krista Rombouts Liver International.2025;[Epub] CrossRef
Polygenic Risk Score for Metabolic Dysfunction-Associated Steatotic Liver Disease and Steatohepatitis: A Narrative Review Tatsuo Kanda, Reina Sasaki-Tanaka, Hiroyuki Abe, Naruhiro Kimura, Tomoaki Yoshida, Kazunao Hayashi, Akira Sakamaki, Takeshi Yokoo, Hiroteru Kamimura, Atsunori Tsuchiya, Kenya Kamimura, Shuji Terai International Journal of Molecular Sciences.2025; 26(11): 5164. CrossRef
Gelsolin's Protective Role in MASH through F‐Actin Regulation and P53 Degradation Yiwei Lu, Tong Ji, Zhichao Ye, Jianing Yan, Chao Wang, Jiachen Chen, Ziyang Jin, Yongji Zhu, Xiujun Cai, Yifan Wang Advanced Science.2025;[Epub] CrossRef
Emerging therapies and real-world application of metabolic dysfunction-associated steatotic liver disease treatment Hee Yeon Kim, Mary E. Rinella Clinical and Molecular Hepatology.2025; 31(3): 753. CrossRef
Multi-omics reveals total flavones from Abelmoschus manihot (L.) Medik. [Malvaceae] ameliorate MAFLD via PI3K/AKT/mTOR-mediated autophagy Chao Lv, Lei Zhao, Jiani Hou, Hongyin Sun, Zhongsha Li, Yuesong Wu, Peizheng Shi, Yaping Xiao, Yunjin Xie, Wei Su, Mingzhu Yin Frontiers in Pharmacology.2025;[Epub] CrossRef
The Distribution and Survival Association of Genetic Polymorphisms in Thai Patients with Hepatocellular Carcinoma According to Underlying Liver Disease Theint Cho Zin Aung, Bootsakorn Boonkaew, Maneerat Chayanupatkul, Kittiyod Poovorawan, Natthaya Chuaypen, Pisit Tangkijvanich Genes.2025; 16(7): 808. CrossRef
Editorial: Time to Genotype—Genetic Risk and Prognosis in Steatotic Liver Disease Rosellina M. Mancina, Stefano Romeo Alimentary Pharmacology & Therapeutics.2025; 62(8): 841. CrossRef
Human genetics of steatotic liver disease: insights into insulin resistance and lipid metabolism Rosellina M. Mancina, Luca Valenti, Stefano Romeo Nature Metabolism.2025; 7(11): 2199. CrossRef
Lysosome-Targeting Chimeras: Design, Mechanisms, and Degradation of “Rogue” Proteins Muneeb Ur Rehman, Xinxi Wu, Qun Chen, Ziwei Liu, Sihui Long Bioorganic Chemistry.2025; 167: 109249. CrossRef
Unveiling EMC6 as a novel pathogenic determinant in hepatocellular carcinoma: orchestration of lipid metabolism through regulation of lipid droplet-associated enzyme HSD17B13 Yun Zhang, Chanyu Xiong, Zhilin Jiang, Xiao Wang, Zihao Wang, Junyao Chen, Qiong Li, Yangyang Luo, Xudan Yang, Chen Chu, Shikai Zhu, Xianjun Zhu, Yu Zhou Oncogene.2025;[Epub] CrossRef
Pharmacotherapy of Liver Fibrosis and Hepatitis: Recent Advances Liangtao Zhao, Haolan Tang, Zhangjun Cheng Pharmaceuticals.2024; 17(12): 1724. CrossRef
Amal Magdy, Hee-Jin Kim, Hanyong Go, Jun Min Lee, Hyun Ahm Sohn, Keeok Haam, Hyo-Jung Jung, Jong-Lyul Park, Taekyeong Yoo, Eun-Soo Kwon, Dong Hyeon Lee, Murim Choi, Keon Wook Kang, Won Kim, Mirang Kim, on behalf of the Innovative Target Exploration of NAFLD (ITEN) Consortium
Clin Mol Hepatol 2024;30(4):824-844. Published online July 25, 2024
Background/Aims Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction–associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD.
Methods Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction–associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing.
Results Methylome and transcriptome analyses of liver biopsies revealed significant (P<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA, and SERPING1, as well as hypomethylation (P<0.0005) and upregulation (P<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data.
Conclusions Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.
Role of genetic variants and DNA methylation of lipid metabolism-related genes in metabolic dysfunction-associated steatotic liver disease Jun-Jie Wang, Xiao-Yuan Chen, Yi-Rong Zhang, Yan Shen, Meng-Lin Zhu, Jun Zhang, Jun-Jie Zhang Frontiers in Physiology.2025;[Epub] CrossRef
Uncovering hepatic transcriptomic and circulating proteomic signatures in MASH: A meta-analysis and machine learning-based biomarker discovery Elena Cristina Rusu, Helena Clavero-Mestres, Mario Sánchez-Álvarez, Marina Veciana-Molins, Laia Bertran, Pablo Monfort-Lanzas, Carmen Aguilar, Javier Camaron, Teresa Auguet Computers in Biology and Medicine.2025; 191: 110170. CrossRef
Sepsis-related immune signature C3 in endometrial carcinoma: implications for prognosis, tumor progression through bioinformatics and experimental validation Kulsoom, Wajahat Ali, Saleem Ahmad, Irfan Ali Khan, Tanveen Kaur Soni, Asia Masood, Muhammad Omer Iqbal, Valisher Sapayev Odilbek uglu, Mukhayya Xusinovna Djumaniyazova, Anas Sameed Cholavaram, Mubaraq Arisekola Abdulrahmon Molecular Biology Reports.2025;[Epub] CrossRef
Gradual DNA methylation changes reveal transcription factors implicated in metabolic dysfunction-associated steatotic liver disease progression and epigenetic age acceleration Evelien Van Dijck, Steven Van Laere, Emilie Logie, Steven Timmermans, Erik Fransen, Joe Ibrahim, Timothy J. Kendall, Jonathan A. Fallowfield, Ligia M. Mateiu, Claude Libert, Guy Van Camp, An Verrijken, Luc Van Gaal, Sven Francque, Wim Van Hul, Wim Vanden Clinical Epigenetics.2025;[Epub] CrossRef
Recent progress in histone post-translational modifications as regulators of metabolic diseases: A review Aiqiang Zhu, Tong Ye, Minjia Tan, Jun-Yu Xu International Journal of Biological Macromolecules.2025; 330: 147964. CrossRef
Background/Aims Bariatric intervention has been reported to be an effective way to improve metabolic dysfunction-associated steatotic liver disease (MASLD) in obese individuals. The current systemic review aimed to assess the changes in MRI-determined hepatic proton density fat fraction (MRI-PDFF) and nonalcoholic fatty liver disease activity score (NAS) after bariatric surgery or intragastric balloon/gastric banding in MASLD patients with obesity.
Methods We searched various databases including PubMed, OVID Medline, EMBASE, and Cochrane Library. Primary outcomes were the changes in intrahepatic fat on MRI-PDFF and histologic features of metabolic dysfunction-associated steatohepatitis (MASH).
Results Thirty studies with a total of 3,134 patients were selected for meta-analysis. Bariatric intervention significantly reduced BMI (ratio of means, 0.79) and showed 72% reduction of intrahepatic fat on MRI-PDFF at 6 months after bariatric intervention (ratio of means, 0.28). Eight studies revealed that NAS was reduced by 60% at 3–6 months compared to baseline, 40% at 12–24 months, and 50% at 36–60 months. Nineteen studies revealed that the proportion of patients with steatosis decreased by 44% at 3–6 months, 37% at 12–24 months, and 29% at 36–60 months; lobular inflammation by 36% at 12–24 months and 51% at 36–60 months; ballooning degeneration by 38% at 12–24 months; significant fibrosis (≥F2) by 18% at 12–24 months and by 17% at 36–60 months after intervention.
Conclusions Bariatric intervention significantly improved MRI-PDFF and histologic features of MASH in patients with obesity. Bariatric intervention might be the effective alternative treatment option for patients with MASLD who do not respond to lifestyle modification or medical treatment.
Citations
Citations to this article as recorded by
Serial changes in metabolic dysfunction-associated steatotic liver disease after sleeve gastrectomy and their associations with abdominal adiposity: a prospective cohort study Chung-Yi Yang, Jian-Han Chen, Chung-Yen Chen, Cheng-Yi Kao, Shiu-Feng Huang, Wen-Yu Chang, Hung-Pin Tu, Jee-Fu Huang, Ming-Lung Yu, Chi-Ming Tai Surgery for Obesity and Related Diseases.2025; 21(5): 537. CrossRef
Bariatric nutrition and evaluation of the metabolic surgical patient: Update to the 2022 Obesity Medicine Association (OMA) bariatric surgery, gastrointestinal hormones, and the microbiome clinical practice statement (CPS) Sue Benson-Davies, Kirsten Frederiksen, Rutuja Patel Obesity Pillars.2025; 13: 100154. CrossRef
Letter to the editor on “Bariatric intervention improves metabolic dysfunction-associated steatohepatitis in patients with obesity: A systematic review and meta-analysis” Xiao-Song Li, Xi-Ping Shen, Hang Li Clinical and Molecular Hepatology.2025; 31(1): e15. CrossRef
Correspondence to letter to the editor on “Bariatric intervention improves metabolic dysfunction-associated steatohepatitis in patients with obesity: A systematic review and meta-analysis” Yuri Cho, Dae Won Jun Clinical and Molecular Hepatology.2025; 31(1): e103. CrossRef
Glucagon like peptide-1 receptor agonists as a promising therapeutic option of metabolic dysfunction associated steatotic liver disease and obesity: hitting two targets with one shot Eda Kaya, Wing-Kin Syn, Paul Manka Current Opinion in Gastroenterology.2025; 41(3): 104. CrossRef
Perioperative Screening for Metabolic Dysfunction Associated Steatotic Liver Disease in People Undergoing Bariatric Surgery: A Pilot Study David M. Williams, Thinzar Min, Andrew Beamish, Jeffrey W. Stephens Obesity Surgery.2025; 35(5): 1963. CrossRef
Impact of Severity of Metabolism-Related Fatty Liver Disease Based on Pathologic Grading on Outcomes after Sleeve Gastrectomy 云飞 曲 Journal of Clinical Personalized Medicine.2025; 04(02): 826. CrossRef
Cambios biométricos y metabólicos a un año de seguimiento en pacientes con obesidad e hígado graso sometidos a gastroplastia endoscópica en manga-EndoSleeve (método Apollo) Diego Schwarzstein, Lissette Batista, Patricia Gonçalves, Luis Yip, Leoniana Bustillos, Mar Bacardit, Josep Merlo Revista de la Sociedad Española de Cirugía de Obesidad y Metabólica y de la Sociedad Española para el Estudio de la Obesidad.2025;[Epub] CrossRef
Liver and obesity: a narrative review Amedeo Lonardo, Ralf Weiskirchen Exploration of Medicine.2025;[Epub] CrossRef
Incretins and MASLD: at the Crossroads of Endocrine and Hepatic Disorders Marwin A. Farrugia, Enzo Pini, Albert Tran, Nicolas Chevalier, Rodolphe Anty, Philippe Gual Current Obesity Reports.2025;[Epub] CrossRef
Comparative effectiveness of tirzepatide versus bariatric metabolic surgery in adults with metabolic-associated steatotic liver disease and obesity: a multi-institutional propensity score-matched study Jheng-Yan Wu, Yu-Min Lin, Wan-Hsuan Hsu, Ting-Hui Liu, Ya-Wen Tsai, Po-Yu Huang, Min-Hsiang Chuang, Tsung Yu, Chih-Cheng Lai Hepatology International.2025; 19(5): 1087. CrossRef
Exploring the role of xanthine oxidase and aldehyde oxidase in metabolic dysfunction-associated steatotic liver disease (MASLD) Neha Gupta, Kavita Singh Journal of Molecular Histology.2025;[Epub] CrossRef
Diabetes mellitus as a multisystem disease: understanding subtypes, complications, and the link with steatotic liver diseases in humans Anna Giannakogeorgou, Michael Roden, Kalliopi Pafili Hormones.2025;[Epub] CrossRef
Duodenal mucosal ablation: An emerging therapeutic concept for metabolic dysfunction-associated fatty liver disease Cornelius J Fernandez, Sweekruti Jena, Vijaya Lakshmi, Joseph M Pappachan World Journal of Gastroenterology.2025;[Epub] CrossRef
Multiparametric MRI Evaluation of Liver Fat and Iron after Glucagon-like Peptide-1 Receptor and Glucagon Receptor Dual-Agonist Treatment in a High-Fat Diet–induced Mouse Model Huimin Xia, Yuqin Min, Yuhua Wang, Siyu Gao, Hailing Wang, Fuhua Yan, Ruixin Liu, Jiqiu Wang, Xuejiang Gu, Tingting Bo Radiology.2025;[Epub] CrossRef
Cirrhotic Cardiomyopathy: Bridging Hepatic and Cardiac Pathophysiology in the Modern Era Dragoș Lupu, Camelia Cornelia Scârneciu, Diana Țînț, Cristina Tudoran Journal of Clinical Medicine.2025; 14(17): 5993. CrossRef
ISImatsuda as a potential predictor of metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes mellitus Jing Liu, Yueqiu Wang, Xinghang Zhou, Zaixin Wen, Yu Chen, Yiqiong Sun, Shuaiying Su, Weiwei Lin, Ruiting Shen, Xiaoyu Sun, Hongru Li, Xia Yu, Mingchen Zhang Frontiers in Medicine.2025;[Epub] CrossRef
Connecting the Dots: Hepatic Steatosis as a Central Player in the Choreography of the Liver-Cardiovascular-Kidney-Metabolic Syndrome Richard H. Goodheart, Oyekoya T. Ayonrinde Heart, Lung and Circulation.2025; 34(10): 1050. CrossRef
Prospective evaluation of a structured group education programme for patients with metabolic dysfunction-associated steatotic liver disease (MASLD) Thomas Crame, Rachel Howarth, Elizabeth Johnstone, Hollie Smith, Stuart McPherson, Kate Hallsworth Frontline Gastroenterology.2025; : flgastro-2025-103280. CrossRef
Endoscopic Bariatric Therapies for Metabolic Dysfunction-Associated Steatotic Liver Disease: Mechanistic Insights and Metabolic Implications Wissam Ghusn, Mira Sridharan, Rachel Fromer, Muhammet Ozdemir, Madeleine G. Haff, Eric J. Vargas Biomedicines.2025; 13(10): 2437. CrossRef
Metabolic Dysfunction–Associated Steatotic Liver Disease in Adults Herbert Tilg, Salvatore Petta, Norbert Stefan, Giovanni Targher JAMA.2025;[Epub] CrossRef
Emerging mechanisms of non-alcoholic steatohepatitis and novel drug therapies Hao CHEN, Yang ZHOU, Haiping HAO, Jing XIONG Chinese Journal of Natural Medicines.2024; 22(8): 724. CrossRef
Weight Loss After Sleeve Gastrectomy According to Metabolic Dysfunction-Associated Steatotic Liver Disease Stage in Patients with Obesity: A Liver Biopsy-Based Prospective Study José Ignacio Martínez-Montoro, Isabel Arranz-Salas, Carolina Gutiérrez-Repiso, Ana Sánchez-García, Luis Ocaña-Wilhelmi, José M. Pinazo-Bandera, Diego Fernández-García, Araceli Muñoz-Garach, Dieter Morales-García, Miren García-Cortés, Eduardo García-Fuente Nutrients.2024; 16(22): 3857. CrossRef
Early portal hypertension in metabolic dysfunction-associated steatotic liver disease: a concise review Iván López-Méndez, Eva Juárez-Hernández, Juan Pablo Soriano-Márquez, Misael Uribe, Graciela Castro-Narro Expert Review of Gastroenterology & Hepatology.2025; 19(7): 755. CrossRef
The effects of next generation probiotics on metabolic dysfunction-associated steatotic liver disease: a parallel, double-blind, randomized, placebo-controlled trial Sung-Min Won, Hyunchae Joung, In Gyu Park, Sang Hak Han, Young Lim Ham, Ji Sook Han, Yoojin Kwon, Dong Joon Kim, Ki Tae Suk Journal of Translational Medicine.2025;[Epub] CrossRef
Correspondence on Editorial regarding “Identification of signature gene set as highly accurate determination of MASLD progression” Sungju Jung, Sumin Yoon, Jong Hoon Park, Yeon-Su Lee, Kyung Hyun Yoo Clinical and Molecular Hepatology.2024; 30(2): 287. CrossRef
First
Prev
