Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, affecting over 30% of the global population, associated with increasing morbidity and mortality [
1,
2]. It is defined by an excess accumulation of intrahepatic lipids, which carries the risk of progression to liver fibrosis or several comorbidities such as type 2 diabetes and cardiovascular diseases [
3]. Countless studies have been conducted to find the holy grail of MASLD treatment. Resmetirom, the first approved treatment for metabolic dysfunction-associated steatohepatitis (MASH), promotes hepatic lipid metabolism and improves steatosis, but shows only limited benefit in patients with early, non-cirrhotic fibrosis [
4]. Similarly, semaglutide, a recently approved GLP-1 agonist for MASH, provides metabolic benefits but is constrained by loss of lean body mass in non-obese patients [
5]. These limitations underscore the need for additional strategies that target the specific metabolic derangements driving MASLD.
Among these derangements, impaired mitochondrial fatty acid β-oxidation is considered central. Carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme for fatty acid entry to mitochondria has long been recognized as a critical node in lipid catabolism. Hepatocyte-specific ablation of CPT1A robustly induces hepatic triglyceride accumulation [
6,
7], whereas constitutively active mutation of CPT1A efficiently ameliorates steatosis in preclinical models [
8]. Despite its pivotal role in lipid catabolism, certain limitations remain in applying CPT1A as a pharmacological target for MASLD. Etomoxir and perhexiline were developed as small-molecule inhibitors that mimic the palmitoyl moiety and compete for the binding pocket of CPT1A [
9,
10]. While these agents confirmed the druggability of CPT1A, their pharmacological action is inhibitory and thus counterproductive in the context of MASLD, where enhanced CPT1A activity followed by increased fatty acid oxidation is desirable. In principle, allosteric activation of CPT1A would provide metabolic benefit; however, despite substantial efforts, no specific CPT1A activator has been successfully developed to date [
11]. This gap highlights the importance of exploring alternative strategies, such as targeting the regulatory mechanisms that control CPT1A protein stability and degradation.
In this context, a study by Lin et al. [
12] represents a conceptual advance by identifying ankyrin repeat and SOCS box protein 3 (ASB3) as the first E3 ligase that mediates CPT1A degradation in the liver. Through proteomic and biochemical approaches, the authors reveal that ASB3 directly ubiquitinates CPT1A at lysine residues 180 and 639, promoting its proteasomal degradation. Importantly, ASB3 expression is elevated in human MASLD livers and inversely correlated with CPT1A levels, establishing translational relevance (
Fig. 1). Hepatocyte-specific deletion of ASB3 enhanced β-oxidation, improved insulin sensitivity, and attenuated both steatosis and fibrosis in dietary models of MASLD, demonstrating that ASB3 acts as a pathogenic regulator of lipid metabolism. This finding is significant for several reasons. First, it uncovers a previously unrecognized posttranslational checkpoint for CPT1A regulation, providing mechanistic insight into why CPT1A protein levels decline in MASLD despite relatively preserved transcript levels [
13]. Second, it introduces ubiquitin signaling into the landscape of MASLD pathogenesis, a domain previously dominated by transcriptional and metabolic regulators. Third, it establishes ASB3 as a potentially druggable node. While other E3 ligases, such as RNF2, have been implicated in CPT1A regulation in oncologic settings [
14], ASB3 represents the first to be functionally validated in hepatocyte metabolism and disease progression.
The therapeutic implications are broad. Pharmacological inhibition of ASB3 could, in principle, stabilize CPT1A and restore mitochondrial oxidative capacity, thereby alleviating lipid accumulation. Unlike direct CPT1A inhibitors such as perhexiline, which face challenges of isoform selectivity and off-target binding [
15], targeting the degradation machinery may yield superior specificity. Moreover, as CPT1A is a mitochondrial outer membrane protein, its ubiquitination may not only determine protein turnover but also intersect with mitophagy and mitochondrial dynamics. CPT1A has been shown to facilitate PINK1-Parkin-dependent mitophagy [
16] and stabilize mitochondrial fission factor [
17]j; thus, ASB3 inhibition might rescue mitochondrial quality control in addition to promoting lipid oxidation. This may be particularly relevant given the recognized impairment of mitophagy and fission in MASH [
18,
19].
Yet, several questions remain. One report demonstrated that liver-specific CPT1A deletion improves glucose tolerance and insulin tolerance by increased secretion of FGF21, indicating that indiscriminate stabilization of CPT1A could have context-dependent consequences [
6]. In addition, ASB3 is highly expressed in multiple organs which complicates the development of systemically administered inhibitors from an on-target safety standpoint. Therefore, strategies such as hepatocyte-specific prodrugs or PROTAC-based approaches may be required to achieve therapeutic selectivity, which warrant further investigations. Nonetheless, the identification of ASB3 as an E3 ligase for CPT1A introduces a novel regulatory axis in hepatic lipid metabolism. By linking ubiquitin-mediated degradation to mitochondrial β-oxidation, Lin et al. [
12] expand the conceptual framework of MASLD pathogenesis and offer a new therapeutic paradigm. Targeting ASB3 represents a promising, MASLD-specific approach that may complement existing interventions directed at lipogenesis or incretin pathways. Future research aimed at clarifying tissue specificity, downstream effects on mitochondrial quality control, and optimal modalities of ASB3 inhibition will determine whether this discovery can be translated into clinical advances.
FOOTNOTES
-
Authors’ contribution
Conception of the work and critical revision: HJR, JHK; Drafting the article: HJR, JSH.
-
Acknowledgements
This work was supported by the National Research Foundation of Korea grant (RS-2024-00348340) and the Korea Basic Science Institute (National Research Facilities and Equipment Center) grant (RS-2024-00398668) funded by the Korea government (MSIT), as well as by the Creative-Pioneering Researchers Program from Seoul National University. J.S.H. was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2025-25421387).
-
Conflicts of Interest
The authors have no conflicts to disclose.
Figure 1.ASB3 promotes degradation of CPT1A by ubiquitination, impeding hepatic fatty acid oxidation in MASLD. CPT1A facilitates the mitochondrial import of fatty acids by transferring the acyl group from acyl-CoA to L-carnitine. Within mitochondria, acyl-carnitine is reconverted to acyl-CoA and subjected to β-oxidation, with the resulting products further oxidized in the tricarboxylic acid cycle. In the livers of MASLD patients and diet-induced MASLD model mice, ASB3 expression is upregulated, promoting ubiquitination and proteasomal degradation of CPT1A. This process compromises mitochondrial fatty acid import and lipid catabolism. Given the reported role of CPT1A in mitochondrial dynamics, its degradation may further impair mitochondrial fission and quality control mechanisms. ASB3, ankyrin repeat and SOCS box protein 3; CPT1A, carnitine palmitoyltransferase 1A; MASLD, metabolic dysfunction-associated steatotic liver disease; TCA, tricarboxylic acid; MCD, methionine/choline deficient; GAN, Gubra Amylin nonalcoholic steatohepatitis.
Abbreviations
ankyrin repeat and SOCS box protein 3
carnitine palmitoyltransferase 1A
metabolic dysfunction-associated steatohepatitis
metabolic dysfunction-associated steatotic liver disease
REFERENCES
- 1. Riazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2022;7:851-861.
- 2. Targher G, Valenti L, Byrne CD. Metabolic dysfunction-associated steatotic liver disease. N Engl J Med 2025;393:683-698.
- 3. Steinberg GR, Valvano CM, De Nardo W, Watt MJ. Integrative metabolism in MASLD and MASH: pathophysiology and emerging mechanisms. J Hepatol 2025;83:584-595.
- 4. Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med 2024;390:497-509.
- 5. Long MT, Noureddin M, Lim JK. AGA clinical practice update: diagnosis and management of nonalcoholic fatty liver disease in lean individuals: expert review. Gastroenterology 2022;163:764-774.e1.
- 6. Sun W, Nie T, Li K, Wu W, Long Q, Feng T, et al. Hepatic CPT1A facilitates liver-adipose cross-talk via induction of FGF21 in mice. Diabetes 2022;71:31-42.
- 7. Zelows MM, Cady C, Dharanipragada N, Mead AE, Kipp ZA, Bates EA, et al. Loss of carnitine palmitoyltransferase 1a reduces docosahexaenoic acid-containing phospholipids and drives sexually dimorphic liver disease in mice. Mol Metab 2023;78:101815.
- 8. Weber M, Mera P, Casas J, Salvador J, Rodríguez A, Alonso S, et al. Liver CPT1A gene therapy reduces diet-induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD. FASEB J 2020;34:11816-11837.
- 9. Kennedy JA, Unger SA, Horowitz JD. Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone. Biochem Pharmacol 1996;52:273-280.
- 10. Selby PL, Sherratt HS. Substituted 2-oxiranecarboxylic acids: a new group of candidate hypoglycaemic drugs. Trends Pharmacol Sci 1989;10:495-500.
- 11. Su W, Xu F, Zhong J, Hu R, Wang L, Li H, et al. Screening of CPT1A-targeting lipid metabolism modulators using mitochondrial membrane chromatography. ACS Appl Mater Interfaces 2024;16:13234-13246.
- 12. Lin Y, Hou W, Ge M, Wu Z, Huang L, Liu H, et al. Hepatocytic ankyrin repeat and SOCS box protein 3 deficiency alleviates metabolic dysfunction-associated steatotic liver disease by decreasing ubiquitin-mediated carnitine palmitoyl transferase 1A. Clin Mol Hepatol 2025;31:1333-1354.
- 13. Kim S, Lee I, Piao S, Nagar H, Choi SJ, Kim YR, et al. miR204 potentially promotes non-alcoholic fatty liver disease by inhibition of cpt1a in mouse hepatocytes. Commun Biol 2022;5:1002.
- 14. Tian T, Lu Y, Lin J, Chen M, Qiu H, Zhu W, et al. CPT1A promotes anoikis resistance in esophageal squamous cell carcinoma via redox homeostasis. Redox Biol 2022;58:102544.
- 15. Schlaepfer IR, Joshi M. CPT1A-mediated fat oxidation, mechanisms, and therapeutic potential. endocrinology 2020;161:bqz046.
- 16. Li S, Liu M, Chen J, Chen Y, Yin M, Zhou Y, et al. L-carnitine alleviates cardiac microvascular dysfunction in diabetic cardiomyopathy by enhancing PINK1-Parkin-dependent mitophagy through the CPT1a-PHB2-PARL pathways. Acta Physiol (Oxf) 2023;238:e13975.
- 17. Zhu Y, Wang Y, Li Y, Li Z, Kong W, Zhao X, et al. Carnitine palmitoyltransferase 1A promotes mitochondrial fission by enhancing MFF succinylation in ovarian cancer. Commun Biol 2023;6:618.
- 18. Yamada T, Murata D, Adachi Y, Itoh K, Kameoka S, Igarashi A, et al. Mitochondrial stasis reveals p62-mediated ubiquitination in Parkin-independent mitophagy and mitigates nonalcoholic fatty liver disease. Cell Metab 2018;28:588-604.e5.
- 19. Fromenty B, Roden M. Mitochondrial alterations in fatty liver diseases. J Hepatol 2023;78:415-429.
Citations
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