An international collaborative study led by Chinese researchers at Wuhan University is the first to have discovered a new small molecule, termed IMA-1, and shown it to be safe and effective for the treatment of nonalcoholic steatohepatitis (NASH) in mouse and macaque models.

These study findings provide proof of concept for the use of a new class of small-molecule inhibitors as next-generation drugs for treating NASH, the authors reported in the Dec. 15, 2021, edition of Science Translational Medicine.

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease worldwide and NASH, its progressive subtype, may lead to cirrhosis and hepatocellular carcinoma (HCC).

"The increasing incidence of NASH is predominantly driven by life style changes, such as diet," said study co-corresponding author Xiao-Jing Zhang, a professor in the School of Basic Medical Sciences at Wuhan University.

This is of concern, as "approximately 15-25% of NASH patients might be expected to progress to cirrhosis and HCC within 10 years of follow-up," Zhang told BioWorld Science.

However, an incomplete understanding of NASH pathogenesis and the failure of clinical translation from small-animal studies have restricted the development of drugs for NASH, for which no effective pharmacological approaches are available.

Therefore, system-based research, mechanism-guided discovery, and validation of efficacy in large animals may lead to successful NASH drug development.

The present study has established that the arachidonate 12-lipoxygenase (ALOX12)-acetyl-coenzyme A (CoA) carboxylase 1 (ACC1) axis is a key driver of NASH progression.

ALOX12 is also known to be involved in liver injuries, including hepatic ischemia reperfusion injury and carbon tetrachloride-associated liver damage, while depletion of the Alox12 gene has been shown to impair glucose uptake in brown adipocytes.

"The latter study was particularly interesting as it has revealed an enzymatic activity-based regulation of metabolic homeostasis by ALOX12 in brown fat, which may lead the development of new metabolic disease therapies," said Zhang.

"In fact, ALOX12 is a promising therapeutic target for different metabolic disorders and organ injury, including NASH, myocardial ischemia-reperfusion, hepatic ischemia and tumor progression."

The experimental small-molecule enzymatic inhibitor of ALOX12, ML-355, can effectively ameliorate thrombosis, platelet aggregation and pancreatic islet cell dysfunction, but it is unknown whether it could also affect the nonenzymatic activity of ALOX12 and its interaction with ACC1.

Nonetheless, studies have established ACC1 as an attractive therapeutic target for NASH, due to improved hepatic steatosis and fibrosis seen with ACC inhibitors both experimentally and in clinical trials.

"ACC1 inhibitors used in clinical trials have included ND-630 (Gilead Sciences), PF-05221304 (Pfizer) and MK-4074 (MSD), all of which cause hyperlipidemia," said Zhang.

Because ACC inhibitor-induced hyperlipidemia has largely restricted clinical use, resolving this without compromising anti-NASH efficacy would optimize the clinical translational potential of ACC inhibitors for NASH therapy.

In the new study, researchers led by Hongliang Li, a professor in the Department of Cardiology at the Renmin Hospital of Wuhan University, identified IMA-1 as being responsible for the therapeutic anti-NASH effect of ML-355 by interrupting ALOX12 and ACC1 interaction in mice and macaques.

"Initially, we showed that ML-355 exhibited a robust anti-NASH effect in mice and monkeys, but had negligible effects in vitro, leading us to hypothesize that ML-355 activity may be attributable to an endogenic metabolite," explained Zhang.

"IMA-1 was then identified as a unique metabolite of ML-355, as demonstrated in monkeys and in a liver microsomes system."

"We then showed that IMA-1 had potent anti-NASH activity, both in vivo and in vitro, and that it could directly bind to ALOX12 and interrupt ALOX12-ACC1 interaction, as shown using isothermal titration calorimetry and co-immunoprecipitation assays."

Notably, IMA-1 was shown markedly to block diet-induced NASH progression in mice and cynomolgus macaque therapeutic models, with the anti-NASH efficacy of IMA-1 being comparable to ACC1 inhibition in both models.

"The protective effect of IMA-1 on NASH was very robust, with an approximately 80% decline in liver lipid accumulation in mice and almost total reversal of hepatic steatosis and fibrosis in macaque monkeys," Zhang said.

Mechanistically, protein docking simulations and functional experiments suggested that the anti-NASH effects of IMA-1 were largely dependent on its direct binding to a pocket in ALOX12 proximal to its ACC1-interacting surface, rather than inhibiting ALOX12 lipoxygenase activity.

Therefore, "rather than depending on the lipoxygenase activity, this shows that ALOX12 promotes NASH progression by directly binding to ACC1 and blocking ACC1 lysosomal degradation," said Zhang.

Importantly, IMA-1 treatment was not found to induce hyperlipidemia, a known side effect of direct ACC inhibition, in either mice or macaques.

Together, these findings provide proof of concept across multiple species for the use of small molecule-based therapies and identify a promising new class of NASH therapeutic compounds (Zhang, X.-J. et al. Sci Transl Med 2021, 13: eabg8116).