Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a growing global health challenge, posing an increasing burden on healthcare systems worldwide. By 2040, the prevalence rate of MASLD in adults is projected to increase to more than 55% [
1]. It is characterized by excessive hepatic lipid accumulation, which can progress to steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma [
2]. At the core of MASLD pathogenesis lies a failure in hepatic lipid homeostasis, which may be attributed to the impaired mitochondrial fatty acid oxidation (FAO) [
3,
4]. Despite its high prevalence, treatment options remain severely limited, highlighting an urgent need to elucidate the precise molecular mechanisms that regulate hepatic lipid metabolism.
Carnitine palmitoyltransferase 1A (CPT1A) is a mitochondrial enzyme that regulates long-chain fatty acid entry into mitochondria for β-oxidation [
5]. By facilitating FAO, CPT1A plays a critical role in maintaining systemic energy balance, particularly during fasting or high-energy-demand states [
6]. Recent studies underscore CPT1A as a metabolic checkpoint. When CPT1A is downregulated, FAO is suppressed, leading to steatosis. Conversely, maintaining CPT1A expression and activity enhances FAO and prevents fat accumulation [
7,
8]. Interestingly, CPT1A activity is reduced in MASLD; however, the mechanisms driving this reduction remained largely unclear until now.
Ankyrin repeat and SOCS box protein 3 (ASB3) belongs to the SOCS-box protein family; its canonical role is to tag specific protein substrates for ubiquitin-mediated degradation [
9,
10]. Earlier studies have demonstrated ASB3’s role in inflammatory pathways and hepatocellular carcinoma. However, its role in lipid metabolism has not been investigated [
11-
13]. In this issue of
Clinical and Molecular Hepatology, Lin et al. [
14] uncovered the role of ASB3 in MASLD, by combining sophisticated in vitro models, genetically engineered mice, and human data to establish a causal link between ASB3, FAO dysfunction, and hepatic steatosis. Their key insight—that ASB3 promotes MASLD by targeting CPT1A for ubiquitin-mediated degradation—fills a long-standing gap in our knowledge of CPT1A regulation.
Lin et al. demonstrated that hepatic ASB3 expression is elevated in MASLD. Hepatocyte-specific ASB3 knockout mice fed a high-fat diet (HFD) exhibited reduced body weight, markedly less hepatic steatosis, improved glucose tolerance, and enhanced insulin sensitivity compared with the controls. This phenotype was intrinsically linked to an increase in energy expenditure, as evidenced by higher oxygen consumption rates, indicating a fundamental enhancement of mitochondrial function. The core mechanistic discovery of this work is the identification of CPT1A as a direct substrate of ASB3. Lin et al. further employed quantitative lysine ubiquitin proteomics to discover that ASB3 specifically mediates the polyubiquitination of CPT1A at two lysine residues (K180 and K639), thereby targeting it for proteasomal degradation [
15]. The authors further solidified this causal relationship by demonstrating that the protective effects of ASB3 knockout—reduced lipid droplets and increased FAO—were completely abolished upon pharmacological inhibition of CPT1A with etomoxir or via AAV-mediated knockdown of CPT1A in the liver. The data from patients with MASLD strongly support the translational relevance of these findings. This research provides a coherent and compelling model: under nutrient-rich conditions, such as an HFD, elevated hepatic ASB3 promotes the ubiquitination and degradation of CPT1A. This dampens mitochondrial FAO, creating a metabolic bottleneck that diverts fatty acids toward esterification and storage as lipid droplets, thereby accelerating MASLD progression. Conversely, inhibiting ASB3 stabilizes CPT1A, unleashes mitochondrial fatty acid oxidation, combusts lipid substrates for energy, and alleviates hepatic steatosis and its downstream consequences (
Fig. 1).
Several questions remain to be explored in future studies. First, the structural basis of the ASB3-CPT1A interaction remains undefined. Understanding how ASB3’s ankyrin repeat domains bind to CPT1A (and why this interaction targets K180 and K639) will be essential for rational drug design. Secondly, the interplay between ASB3-mediated ubiquitination and other post-translational modifications of CPT1A (e.g., phosphorylation, acetylation) is unknown. For example, recent studies have shown that deubiquitinating enzymes like USP50 can stabilize CPT1A; understanding how ASB3 interacts with these regulators could reveal combinatorial therapeutic strategies [
16]. Another question worth exploring is the role of ASB3 in liver fibrosis. Lin et al. demonstrated that hepatocyte-specific ASB3 knockout reduces liver fibrosis in mice fed the MCD diet, but the mechanism linking ASB3 to fibrogenesis remains unclear. Does ASB3 affect hepatic stellate cell activation (the primary drivers of fibrosis) directly, or is its anti-fibrotic effect a secondary consequence of reduced steatosis and inflammation? Answering these questions will be important to determine whether ASB3 inhibitors can treat not only early-stage steatosis but also progressive MASH and fibrosis.
In summary, enhancing CPT1A stability and FAO through ASB3 inhibition offers a promising therapeutic strategy for treating MASLD and related liver diseases. Although several questions remain, this study provides valuable mechanistic insights into MASLD pathogenesis.
FOOTNOTES
-
Authors’ contributions
Yueying Yang conceived and drafted the manuscript. Ying Yang and Yan Lu reviewed and finalized the manuscript.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Figure 1.ASB3 contributes to the pathogenesis and progression of MASLD by regulating the stability of CPT1A. In normal livers, CPT1A mediates the transport of long-chain fatty acids into the mitochondrial matrix for oxidative breakdown. In the livers of MASLD, ASB3 expression is upregulated. This leads to the ubiquitination and destabilization of CPT1A. ASB3-mediated degradation of CPT1A impairs FAO and promotes lipid accumulation. MASLD, metabolic dysfunction-associated steatotic liver disease; FAO, fatty acid oxidation; ASB3, ankyrin repeat and SOCS box protein 3; CPT1A, carnitine palmitoyl transferase 1A.
Abbreviations
ankyrin repeat and SOCS box protein 3
carnitine palmitoyl transferase 1A
metabolic dysfunction-associated steatotic liver disease
REFERENCES
- 1. Younossi ZM, Kalligeros M, Henry L. Epidemiology of metabolic dysfunction-associated steatotic liver disease. Clin Mol Hepatol 2025;31(Suppl):S32-S50.
- 2. Lazarus JV, Mark HE, Anstee QM, Arab JP, Batterham RL, Castera L, et al. Advancing the global public health agenda for NAFLD: a consensus statement. Nat Rev Gastroenterol Hepatol 2022;19:60-78.
- 3. Geng Y, Faber KN, de Meijer VE, Blokzijl H, Moshage H. How does hepatic lipid accumulation lead to lipotoxicity in nonalcoholic fatty liver disease? Hepatol Int 2021;15:21-35.
- 4. Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci 2018;75:3313-3327.
- 5. McGarry JD, Woeltje KF, Kuwajima M, Foster DW. Regulation of ketogenesis and the renaissance of carnitine palmitoyltransferase. Diabetes Metab Rev 1989;5:271-284.
- 6. Schlaepfer IR, Joshi M. CPT1A-mediated fat oxidation, mechanisms, and therapeutic potential. Endocrinology 2020;161:bqz046.
- 7. 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.
- 8. Dong J, Li M, Peng R, Zhang Y, Qiao Z, Sun N. ACACA reduces lipid accumulation through dual regulation of lipid metabolism and mitochondrial function via AMPK-PPARα-CPT1A axis. J Transl Med 2024;22:196.
- 9. Kohroki J, Nishiyama T, Nakamura T, Masuho Y. ASB proteins interact with Cullin5 and Rbx2 to form E3 ubiquitin ligase complexes. FEBS Lett 2005;579:6796-6802.
- 10. Chung AS, Guan YJ, Yuan ZL, Albina JE, Chin YE. Ankyrin repeat and SOCS box 3 (ASB3) mediates ubiquitination and degradation of tumor necrosis factor receptor II. Mol Cell Biol 2005;25:4716-4726.
- 11. Zhang W, Liu F, Che Z, Wu M, Tang Z, Liu J, et al. ASB3 knockdown promotes mitochondrial apoptosis via activating the interdependent cleavage of Beclin1 and caspase-8 in hepatocellular carcinoma. Sci China Life Sci 2019;62:1692-1702.
- 12. Cheng M, Xu B, Sun Y, Wang J, Lu Y, Shi C, et al. ASB3 expression aggravates inflammatory bowel disease by targeting TRAF6 protein stability and affecting the intestinal microbiota. mBio 2024;15:e0204324.
- 13. Huang L, Che Z, Liu F, Ge M, Wu Z, Wu L, et al. ASB3 promotes hepatocellular carcinoma progression by mediating DR5 ubiquitination in TRAIL resistance. FASEB J 2024;38:e23475.
- 14. 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.
- 15. Hör S, Ziv T, Admon A, Lehner PJ. Stable isotope labeling by amino acids in cell culture and differential plasma membrane proteome quantitation identify new substrates for the MARCH9 transmembrane E3 ligase. Mol Cell Proteomics 2009;8:1959-1971.
- 16. Li R, Li X, Zhao J, Meng F, Yao C, Bao E, et al. Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1amediated fatty acid oxidation. Theranostics 2022;12:976-998.
Citations
Citations to this article as recorded by
