Horn, MarilizeGumede, Nontobeko MylletGamede, Mlindeli2025-10-222025-10-222025-11Horn, M., Gumede, N. & Gamede, M. 2025, 'The pathogenesis of metabolic dysfunction-associated steatotic liver disease and nucleoside reverse transcriptase inhibitors (NRTIs) -based HIV-antiretroviral regimens : a comprehensive narrative review', Biomedicine and Pharmacotherapy, vol. 192, art. 118633, pp. 1-16, doi : 10.1016/j.biopha.2025.1186330753-3322 (print)1950-6007 (online)10.1016/j.biopha.2025.118633http://hdl.handle.net/2263/104801DATA AVAILABILITY : No data was used for the research described in the article.Metabolically-dysfunction-associated steatotic liver disease (MASLD) is the result of fat accumulation in > 5 % of hepatocytes, given the absence of excessive alcohol consumption. The metabolic conditions, such as obesity with ectopic fat accumulation, serve as one of the risk factors of MASLD. The pathogenesis of MASLD may be attributed to the impaired systemic lipid metabolism as well as activation of de novo lipogenesis transcription factors, such as ChREBP and SREBP-1C, in the liver. The combined effects of both systemic dyslipidaemia and hyperactive hepatic de novo lipogenesis have been widely associated with the onset and progression of MASLD from steatosis to metabolic dysfunction-associated steatosis hepatitis (MASH). Moreover, systemic insulin resistance and impaired hepatic insulin function also correlate with the onset of MASLD. People living with HIV (PLWHIV) have been reported to be more susceptible to the development of MASLD. However, whether this could be attributed to the chronic use of antiretroviral therapy treatments (ART) or the detrimental effects of the virus remains the subject of research. Over the past decades, different regimens of ART, including highly active antiretroviral therapy (HAART), have been introduced. However, some of the HAART regimen drugs are continually being discontinued citing a variety of side effects, including metabolic derangements. Furthermore, the recent developments on GLP-1 agonists showing the cardioprotective and antidiabetic effects have elicited increasing interest in their potential repurposing for the treatment of MASLD. The preventative measures for MASLD will be imperative in the future, and this may include constant monitoring of hepatic de novo lipogenesis markers in individuals on chronic medications such as ART. HIGHLIGHTS • The PLWHIV and on ART have increased risks of developing MASLD. • HIV-ART might lead to the onset of MASLD via mitochondrial dysfunction-induced hepatotoxicity. • The ART could be possible driving the de novo hepatic lipogenesis through activation of ChREBP and SREBP-1c. • Resmetirom and GLP-1 agonists provide novel therapeutic targets for MASLD. • There is a possible autonomous link between HIV-ART and the pathogenesis of MASLD.en© 2025 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Metabolically-dysfunction-associated steatotic liver disease (MASLD)Metabolic dysfunction-associated steatosis hepatitis (MASH)People living with HIV (PLWHIV)Antiretroviral therapy (ART)Highly active antiretroviral therapy (HAART)Insulin resistanceDyslipidaemiaAntiretrovirals (ARVs)HepaticMetabolic syndromeArticle