Hepatic HSD17B6 promotes lipid accumulation and M1 macrophage polarization via the 9-cis-retinoic acid and RXRα axis.

Authors

Xiaona Cheng, Kaikai Lu, Zizhen Guo, Luyun Yang, Keyu Yang, Kexin Cheng, Litao Wu, Chunyan Yin, Muhammad Shahzad, Dongmin Li

Published in

Free radical biology & medicine. Oct 14, 2026. Epub Oct 14, 2026.

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly prevalent and lacks effective therapies. Hydroxysteroid 17-beta dehydrogenase 6 (HSD17B6), a liver-enriched enzyme involved in retinoid and steroid metabolism, has not been functionally characterized in MASH pathogenesis.
Transcriptomic analysis of PDCD4-deficient livers identified HSD17B6 as a key upregulated gene. Its expression was validated in human MASH liver samples and murine MASH models and localized primarily to hepatocytes via single-cell RNA sequencing. Hepatic 9-cis-retinoic acid (9cRA) was quantified by HPLC. Functional consequences of HSD17B6 modulation were assessed in stable gain- and loss-of-function hepatocyte models. Underlying mechanisms were dissected using siRNA silencing and pharmacological inhibitors.
PDCD4 deficiency upregulated HSD17B6, leading to increased hepatic 9cRA. 9cRA activated the nuclear receptor RXRα, which in turn promoted lipid accumulation by transactivating genes such as SCD1 and CD36. Concurrently, RXRα activation directly stimulated the transcription and secretion of the chemokine CXCL10 from hepatocytes, which drove M1 macrophage polarization via CXCR3. Both genetic and pharmacological inhibition of RXRα effectively mitigated HSD17B6-driven lipid dysregulation and macrophage-mediated inflammation.
Using a PDCD4-deficient mouse model and complementary in vitro and human data, this study identifies HSD17B6 as an important contributor to hepatic lipid accumulation and inflammation in MASH. Mechanistically, HSD17B6 promotes these pathological processes through modulation of the 9cRA-RXRα signaling axis. These findings provide new insights into the metabolic-inflammatory crosstalk underlying MASH progression and suggest that the HSD17B6-RXRα pathway may represent a potential therapeutic target for mitigating hepatic steatosis and inflammation.

PMID:
42874884
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.