Chinese Medical Journal study uncovers new mechanism for liver fibrosis treatment

Liver fibrosis is a common progressive pathological process of different chronic liver injuries, which can further progress to cirrhosis and even liver cancer, posing a serious threat to patients' lives. However, no effective therapy is currently available to patients. Thus, elucidating the pathological mechanisms of liver fibrosis and identifying novel molecular therapeutic targets and drugs have become key priorities in current liver disease research.

Recently, a research team led by Professor Qian Li from the Medical School of Yangzhou University revealed that dihydroartemisinin upregulates the expression of CHAC1 through H3K9 acetylation modification, thereby inducing ferroptosis in hepatic stellate cells (HSCs) and suppressing the progression of liver fibrosis. Their study was published in the Chinese Medical Journal on September 15, 2025.

Liver fibrosis, as a complex pathological process, involves the collective participation of various cells and molecules in its occurrence and progression. Previous studies have shown that the activation of HSCs plays a central role in the process of liver fibrosis. Therefore, eliminating activated HSCs has become one of the most effective strategies in liver fibrosis.

Among these most effective strategies, the role of HSC ferroptosis in the pathophysiological mechanisms of liver fibrosis has garnered increasing attention from scholars both domestically and internationally. Ferroptosis is a form of cell death that depends on iron ions and reactive oxygen species to induce lipid peroxidation of the cell membrane, thereby disrupting the structural integrity of the cell membrane and leading to cell death.

Dihydroartemisinin possesses a wide range of pharmacological benefits, including antibacterial, antitumor, and antischistosomal activities. Studies have shown that dihydroartemisinin can exert antifibrotic effects on the liver by inducing ferroptosis in HSCs, thereby inhibiting their activation. However, the precise underlying mechanisms remain unclear.

This study found that the level of the glutathione-specific γ-glutamylcyclotransferase 1 CHAC1 was significantly upregulated in HSCs treated with dihydroartemisinin, while interference with CHAC1 inhibited dihydroartemisinin induced ferroptosis in HSCs. Further research revealed that DHA regulates the expression of CHAC1 at the transcriptional level rather than the post-transcriptional level. Specifically, dihydroartemisinin promoted CHAC1 transcription through H3K9 acetylation, with ATF4 identified as a key transcription factor for CHAC1 transcriptional activation. Moreover, the promoter regions of CHAC1 from -199 bp to -212 bp and -257 bp to -269 bp are essential for ATF4 to initiate transcription.

Prof. Qian Li emphasized, “Our findings show that regulating ferroptosis in hepatic stellate cells is crucial for halting the progression of liver fibrosis and points towards promising therapeutic approaches.” She further commented, “By understanding how dihydroartemisinin activates CHAC1 through H3K9 acetylation, we have identified molecular targets that could help develop new anti-fibrotic drugs in the future.”

In summary, H3K9 acetylation plays a pivotal role in dihydroartemisinin-induced HSC ferroptosis and its antifibrotic effects by transcriptionally activating CHAC1. These findings not only provide a theoretical basis for the clinical application of dihydroartemisinin as an anti-fibrotic drug, but also elucidate the important role of H3K9 acetylation as a novel post-transcriptional regulatory mechanism in dihydroartemisinin-induced ferroptosis.

This study not only offers new insights into the molecular mechanisms underlying dihydroartemisinin-induced ferroptosis, but also identifies potential therapeutic targets for the development of liver fibrosis treatment strategies.

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Reference
DOI: 10.1097/CM9.0000000000003788