An esterase-activated celastrol delivery system suppressed steatosis-related hepatocellular carcinoma progression.

Authors

Zile Shao, Yangla Xie, Yidan Shen, Yiyang Sun, Long Zhang, Nasha Qiu, Xiao Xu

Published in

Biomaterials science. Jun 19, 2026. Epub Jun 19, 2026.

Abstract

The etiological landscape of hepatocellular carcinoma is shifting markedly, with metabolism-associated fatty liver disease (MAFLD) increasingly being regarded as a major pathogenic factor. The pathophysiological relationship between MAFLD and hepatocellular carcinoma (HCC) involves metabolic disorders, such as impaired lipid metabolism; thus, new strategies that simultaneously target abnormal lipid metabolism and HCC are urgently needed. Celastrol (CEL), a traditional Chinese medicine, exhibits significant anticancer activity against various cancers, including HCC. In addition, as a metabolic modulator, CEL enhances leptin receptor sensitivity and improves glucose and lipid metabolism. Thus, we speculate that CEL could be a promising candidate for the effective treatment of steatosis-related HCC. However, the hydrophobicity and low bioavailability of CEL limit its clinical applications. To overcome these obstacles, we developed an esterase-activated CEL-loaded delivery system (PQDMA@CEL NPs) using the amphiphilic cationic polymer poly{N-[2-(acryloyloxy)ethyl]-N-[p-acetyloxyphenyl]-N,N-dimethylammonium chloride} (PQDMA). PQDMA@CEL NPs were efficiently internalized by both hepatocellular and hepatocellular carcinoma cells and underwent esterase-activated charge reversal to release CEL, inducing ferroptosis in HCC cells. Furthermore, in vitro studies showed that the lipid degradation efficacy of PQDMA@CEL NPs was 1.8-fold higher than that of free CEL in steatotic hepatocellular AML12 cells. In the Hepa1-6 bilateral tumor model, a single-site intratumoral injection of PQDMA@CEL NPs systemically boosted the anticancer efficacy. The tumor inhibition rate of PQDMA@CEL NPs was 72.4% for treated tumors and 65.8% for the distant untreated tumors. In summary, this approach provides new insights into the inhibition of steatosis-related HCC progression by inducing ferroptosis and decreasing lipid accumulation in HCC.

PMID:
42319350
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.

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