Zhu Yiming,Zhang Chihao,Huang Mingzhe,Lin Jiayun,Fan Xiao,Ni Tao
Hepatic stellate cells (HSCs) are activated by inflammatory mediators to secrete extracellular matrix for collagen deposition, leading to liver fibrosis. Ferroptosis is iron- and lipid hydroperoxide-dependent programmed cell death, which has recently been targeted for inhibiting liver fibrogenic processes. Tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase that functions as a tumor suppressor in hepatocellular carcinoma, while little is known about its function in liver fibrosis. In the present study, the differential expression of TRIM26 in normal and fibrotic liver tissues was examined based on both online databases and specimens collected from patient cohort. The effects of TRIM26 on HSCs ferroptosis were examined in vitro through evaluating cell proliferation, lipid peroxidation, and expression of key ferroptosis-related factors. In vivo function of TRIM26 in liver fibrosis was examined based on CCl4-induced mice model. We found that TRIM26 was downregulated in fibrotic liver tissues. The overexpression of TRIM26 inhibited HSCs proliferation, promoted lipid peroxidation, manipulated ferroptosis-related factor expressions, and counteracted the effect of iron inhibitor deferoxamine. Moreover, TRIM26 physically interacted with solute carrier family-7 member-11 (SLC7A11), a critical protein for lipid reactive oxygen species (ROS) scavenging, and mediated its ubiquitination. In addition, TRIM26 overexpression induced HSCs ferroptosis and mitigated CCl4-induced liver fibrosis in mice. In conclusion, TRIM26 promotes HSCs ferroptosis to suppress liver fibrosis through mediating the ubiquitination of SLC7A11. The TRIM26-targeted SLC7A11 suppression can be a novel therapeutic strategy for liver fibrosis.
Endometrial cancer (EC) is a common gynecological malignancy characterized by abnormal glucose metabolism. Paeonol (Pae), a natural phenolic compound derived from traditional Chinese medicine, exhibits broad-spectrum antitumor activity. However, its role in modulating glycolysis and the underlying molecular mechanisms in EC remain poorly understood. The effects on EC cell viability (CCK-8), proliferation (EdU), apoptosis (flow cytometry), invasion (transwell), migration (wound healing), and tube formation rate were assessed. Glycolytic parameters were measured using corresponding commercial kits. Protein and mRNA expression levels were determined by Western blotting and RT-qPCR. The interaction between tripartite motif protein 26 ( TRIM26) and lactate dehydrogenase A (LDHA) was investigated through co-immunoprecipitation (Co-IP), cycloheximide (CHX) chase, and ubiquitination assays. A xenograft model was established to examine the in vivo efficacy of Pae. Pae inhibited proliferation, metastasis, tube formation, and glycolysis of EC cells, and induced apoptosis. Pae suppressed EC malignant behaviors by downregulating LDHA expression. TRIM26 promoted ubiquitination-mediated degradation of LDHA. Overexpression of LDHA reversed the tumor-suppressive effects of TRIM26 overexpression in EC cells. TRIM26 knockdown attenuated the antitumor effects of Pae. In vivo experiments demonstrated that Pae inhibited tumor growth and regulated TRIM26/LDHA expression. Pae was found to promote TRIM26 expression, which in turn enhanced TRIM26-mediated ubiquitination and degradation of LDHA, thereby contributing to glycolysis inhibition and suppression of EC progression. These results suggested that Pae might exert its effects by modulating the TRIM26/LDHA axis and supported its potential therapeutic value in EC.
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