Hepatocellular carcinoma (HCC) ranks sixth in cancer prevalence globally and has the third highest fatality rate [1]. The challenges in treating HCC arise from its late detection, high rates of metastasis and recurrence, and unsatisfactory therapeutic outcomes [2]. Therefore, it is imperative to gain a comprehensive understanding of the complex pathogenesis of HCC, exploit innovative diagnostic approaches, and develop novel efficient molecular targets. Ferroptosis, a demise of iron-dependent cell death featured by increased lipid peroxidation, plays a vital role in HCC regulation. System Xc-is always at the core of ferroptosis regulation, responsible for cysteine uptake and glutamate release to control glutathione (GSH) synthesis. Glutathione peroxidase 4 (GPX4) is GSH-dependent reductase and requires the participation of GSH as the substrate, reducing lipid hydroperoxides to exert protective action from ferroptosis [3]. A plethora of studies have extensively documented the anticancer effect of ferroptosis in HCC [4,5]. Specifically, sorafenib, a first-line drug utilized against HCC, has been found to induce ferroptosis. Many researches have directed their efforts toward enhancing susceptibility to sorafenib-induced ferroptosis for better therapeutic efficacy [6,7]. However, the mechanisms in inducing ferroptosis in HCC progression have not been fully elucidated and the potential involved molecules warrants further excavate.

Tripartite motif-containing proteins (TRIMs) belong to the largest family of RING motif-containing E3 ubiquitin ligases and catalyze ubiquitin-chain modification. TRIMs engage in a variety of biological processes such as cell differentiation, immunity, and tumor formation [8]. In hepatocellular carcinoma, TRIM7 directly binds to Src protein and exerts its suppressive role through Src-mTORC1-S6K1 axis [9]. TRIM11 regulates PHLPP1 ubiquitination to aggravate HCC via activating AKT pathway [10]. TRIM25 targets Keap 1 for degradation, thereby activating Nrf2 nuclear import during endoplasmic reticulum stress in HCC [11]. TRIM47 is a member of TRIM C-IV subfamily, possessing typical RING domain and B30.2 domain (so-called PRY/SPRY motif) at the C-terminus. TRIM47 inhibition protects cerebral ischemia-reperfusion damage associated with Caspase 3 and NF-κB pathways [12]. In non-alcoholic fatty liver, TRIM47 binds to CYLD and leads to its ubiquitination degradation, thereby influencing lipid accumulation, insulin resistance and fibrosis [13]. TRIM47 stabilizes PKC-ε/PKD3 axis to induce breast cancer endocrine therapy resistance [14]. Numerous studies have substantiated the correlation between TRIM47 protein and the incidence and malignant advancement of various tumor types [[15], [16], [17], [18]]. There remains a dearth of knowledge regarding the precise molecular mechanism by which TRIM47 operates in hepatocellular carcinoma.

This study uncovered a novel regulatory association between TRIM47 and CDO1 in HCC. Effects of TRIM47 on tumor growth and development were validated both in vitro and in vivo. Specifically, TRIM47 facilitated the oncogenic processes and progression by binding to CDO1 and inducing its degradation dependent on the ubiquitin-proteasome pathway in HCC. The function of TRIM47 in ferroptosis had largely been attributed to its interaction with CDO1, the key enzyme involved in GSH synthesis. It was shown that TRIM47 served as a critical regulator in HCC, offering potential therapeutic target and a theoretical foundation for liver cancer treatment.