Dear Editor,
We sincerely appreciate the editorial by Dr. Yueying Yang, Dr. Ying Yang, and Dr. Yan Lu [
1], which provided insightful commentaries on our recent study published in
Clinical and Molecular Hepatology [
2] regarding the role of Ankyrin repeat and SOCS box protein 3 (ASB3) as an E3 ubiquitin ligase promoting carnitine palmitoyl transferase 1A (CPT1A) degradation via ubiquitination, thereby suppressing mitochondrial fatty acid oxidation and driving hepatic lipid accumulation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD) [
2].
We appreciate the comments that “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”, and our research identified the E3 ubiquitin ligase ASB3 as a critical regulator of CPT1A stability in MASLD. Our data demonstrate that ASB3 directly mediates polyubiquitination of CPT1A at lysine residues K180 and K639, targeting this rate-limiting enzyme of fatty acid oxidation for proteasomal degradation. Hepatocyte-specific ASB3 ablation in high-fat-diet and GAN-diet fed mice substantially reduced hepatic lipid accumulation. These protective effects were mechanistically dependent on CPT1A function as evidenced by their complete abolition upon pharmacological CPT1A inhibition or genetic CPT1A knockdown. Critically, analysis of liver specimens from MASLD patients revealed elevated ASB3 expression inversely correlated with CPT1A protein levels, confirming the clinical relevance of this regulatory axis. Our findings reveal ASB3-driven ubiquitination as a previously unrecognized mechanism suppressing mitochondrial fat metabolism in MASLD and nominate ASB3 as a candidate therapeutic target. Furthermore, the absence of ASB3 also demonstrated a protective effect in the liver cancer model and across-species fat accumulation, suggesting that the interference strategy targeting ASB3 has a much broader application potential [
3,
4].
As the commentary reveals, we have identified several critical issues that require urgent investigation. The structural basis for ASB3’s selective ubiquitination of CPT1A at the K180/K639 sites is unclear. To address this, we are collaborating with structural biology teams to conduct crystallographic studies and computational modelling of the ASB3-CPT1A interface. This multidisciplinary approach aims to map interaction hotspots with atomic-level precision, thereby accelerating the development of targeted therapies that block this pathogenic axis.
We acknowledge that different post-translational modifications may influence the activity of CPT1A via various pathways. However, we consider that ASB3-mediated degradation of CPT1A via the E3 ubiquitin ligase pathway plays a pivotal role in the regulation of hepatic steatosis. This conclusion is supported by direct evidence of K180/K639 site-specific polyubiquitination modifications, as well as by the fact that protection from ASB3 knockout is entirely dependent on CPT1A function. There is also a clinically relevant correlation between elevated hepatic ASB3 levels and reduced CPT1A levels in human patients with MASLD. As commentators have noted, in addition to ubiquitination, other post-translational modifications (PTMs) may also regulate CPT1A activation and degradation. For instance, USP50-mediated stabilisation of CPT1A reveals a critical deubiquitination mechanism in LPS-induced sepsis [
5], whereas acetylation constitutes another key regulatory pathway for CPT1A function under high-fructose diets [
6]. Consequently, in addition to ASB3-mediated degradation, other PTMs may also regulate CPT1A in MASLD, though this requires further validation. If this hypothesis is correct, as the editorial suggests, it could facilitate the development of more effective combination drug therapies targeting multiple sites. However, the safety implications of polypharmacy and the toxicity risks arising from drug interactions must also be considered [
7].
As the editorialists point out, ASB3 in cells other than hepatocytes during the progression of liver fibrosis is rather limited. While our study mainly emphasize the role of ASB3 in hepatic steatosis and its significance as a therapeutic target for MASLD. Our data from hepatocyte-specific ASB3 knockout mice robustly exhibit substantial regression of fibrotic pathology and ameliorated hepatic inflammation in murine MASLD models. This evidence confirms ASB3 targeting as a promising therapeutic strategy for MASLD-associated fibrosis. Mechanistically, our study is more inclined to suggest that the absence of ASB3 affects hepatic steatosis in hepatocytes, thereby improving hepatic fibrosis and inflammation. This is based on IHC staining in humans and mice, where we observed that ASB3 is mainly expressed in hepatocytes. Meanwhile, specific knockout of ASB3 in hepatocytes can effectively alleviate hepatic steatosis. The evidence we present in this study can confirm that the effect of ASB3 on hepatic steatosis is an important factor in regulating the alleviation of liver fibrosis in MASLD, and ASB3 participates in hepatic fibrosis by affecting steatosis in hepatocytes. We do not rule out whether ASB3 can directly participate in the activation of hepatic stellate cells; the hepatic stellate cell-specific Cre mice (such as
Lrat-Cre or
Pdgfrb-Cre mice) may be beneficial for related studies [
8,
9]. Moreover, further work may also help better understand the role of ASB3 in the progression of liver fibrosis by using some non-fatty liver fibrosis models (such as the carbon tetrachloride-induced liver fibrosis model) or conducting ASB3-blocking treatments during the fibrosis stage [
10].
We would like to thank Profs. Yueying Yang, Ying Yang and Yan Lu once again for their invaluable review. Our future work will focus on resolving the molecular basis of the ASB3-CPT1A interaction and the site-specific ubiquitination at K180/K639, as well as investigating the mechanisms underlying the post-translational modifications of CPT1A in the progression of MASLD. We will also investigate the role of ASB3 in tissues other than hepatocytes, as well as its involvement in liver fibrosis. Nevertheless, our study has revealed a novel ubiquitination axis in which hepatic ASB3 drives MASLD pathogenesis by degrading CPT1A and suppressing fatty acid oxidation. This identifies ASB3 as a potential therapeutic target for metabolic liver disease.
FOOTNOTES
-
Authors’ contribution
Manuscript drafting: Yuli Lin. Manuscript edition and final approval: Yuli Lin, Dongqin Yang, Zhihao Wu, Ming Guan, Chunhua Song.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
Ankyrin repeat and SOCS box protein 3
carnitine palmitoyltransferase 1A
metabolic dysfunction-associated steatotic liver disease
posttranslational modifications
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