Exploring the therapeutic potential of a nano micelle containing a carbon monoxide-releasing molecule for metabolic-associated fatty liver disease by modulating hypoxia-inducible factor-1

Metabolic-associated fatty liver disease (MAFLD) encompasses a spectrum of chronic liver diseases, in-cluding steatohepatitis, cirrhosis, and liver cancer. Despite the increasing prevalence and severity of MAFLD, no approved pharmacological interventions are currently available. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) has emerged as a crucial early mediator in the pathogenesis of MAFLD. Previously, we demon-strated the potent anti-inflammatory properties of the nano-designed carbon monoxide (CO) donor, styrene maleic acid copolymer (SMA) encapsulating CO-releasing molecule (SMA/CORM2), which effec-tively suppressed HIF-1 alpha in various inflammatory disorders. Here, we investigated the therapeutic poten-tial of SMA/CORM2 in a mouse model of MAFLD induced by a high-fat methionine-and choline-deficient (HF-MCD) diet. Following 4 weeks of HF-MCD diet consumption, we observed pronounced hepatic lipid accumulation accompanied by disrupted lipid metabolism, polarization of macrophages towards the pro-inflammatory M1 phenotype, activation of the NLRP3 inflammasome, and upregulation of the TGF-beta fi-brosis signaling pathway. Notably, the early and upstream event driving these pathological changes was the upregulation of HIF-1 alpha. Treatment with SMA/CORM2 (10 mg/kg, three times per week) led to a signif-icant increase in CO levels in both the circulation and liver, resulting in remarkable suppression of HIF-1 alpha expression even before the onset of apparent pathological changes induced by the HF-MCD diet. Conse-quently, SMA/CORM2 administration exerted a significantly protective and therapeutic effect on MAFLD. In vitro studies using hepatocytes treated with high concentrations of fatty acids further supported these findings, as knockdown of HIF-1 alpha using short hairpin RNA (shRNA) elicited similar effects to SMA/CORM2 treatment. Collectively, our results highlight the therapeutic potential of SMA/CORM2 in the management of MAFLD through suppression of HIF-1 alpha. We anticipate that SMA/CORM2, with its ability to modulate HIF-1 alpha expression, may hold promise for future applications in the treatment of MAFLD.Statement of significance Carbon monoxide (CO) is a crucial gaseous signaling molecule that plays a vital role in maintaining homeostasis and is a potential target for treating many inflammatory diseases. Developing drug delivery systems that can deliver CO stably and target specific tissues is of great interest. Our team previously de-veloped a nano micellar CO donor, SMA/CORM2, which exhibits superior bioavailability to native CORM2 and shows therapeutic potential in many inflammatory disease models. In this study, we showed that SMA/CORM2, through controlled CO release, significantly ameliorated steatohepatitis and liver fibrosis induced by an HF-MCD diet by suppressing an HIF-1 alpha mediated inflammatory cascade. These findings provide new insight into the anti-inflammatory function of CO and a promising approach for controlling metabolic-associated fatty liver disease.(c) 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.