Hepatocellular Carcinoma (HCC) is a highly lethal primary liver cancer and is one of the most common cancers globally, mainly occurring in patients with chronic liver diseases such as liver cirrhosis caused by hepatitis B or hepatitis C infections. Risk factors for HCC include chronic hepatitis, liver cirrhosis, alcoholic liver disease, non-alcoholic fatty liver disease, exposure to aflatoxins, and genetic factors [1], [2]. Depending on factors such as tumor size and location, patients can choose different treatment options, including surgical resection, liver transplantation, ablation, targeted therapy, immunotherapy, etc [3], [4], [5]. Oxaliplatin (OXA) is a platinum-based anticancer drug used clinically to treat various malignancies [6], including HCC [7]. Therefore, the sensitivity of HCC cells to oxaliplatin is a key factor affecting the treatment outcomes of HCC. However, more than half of HCC patients are limited by chemotherapy resistance. Studies have shown that under chemotherapy pressure, the acetyltransferase NAT10 drives a novel mechanism of HCC chemotherapy resistance by acetylating and stabilizing the metabolic enzyme ACLY at the K468 site, promoting the generation of nuclear acetyl-CoA, and thereby activating drug resistance gene transcription in an epigenetic manner [8]. Exploring the specific molecular mechanisms affecting HCC oxaliplatin sensitivity is crucial for improving therapeutic outcomes.

Ferroptosis is a form of regulated cell death triggered by the excessive accumulation of lipid peroxides, and its occurrence is closely associated with the dysfunction of the cellular antioxidant system [9]. Accumulating evidence indicates that inducing ferroptosis can enhance the sensitivity of tumor cells to chemotherapeutic drugs and plays a crucial role in the drug resistance to various agents, including oxaliplatin (OXA) [10]. For instance, in gastric cancer, the downregulation of DACT3-AS1 in exosomes derived from cancer-associated fibroblasts (CAFs) can inhibit ferroptosis via the miR-181a-5p/SIRT1 signaling pathway, thereby enhancing the resistance of gastric cancer cells to OXA [11]. In HCC, LINC01134 facilitates the recruitment of the transcription factor Nrf2 to the GPX4 promoter region and positively regulates its expression. Inhibition of LINC01134 significantly promotes the accumulation of lipid ROS and malondialdehyde, reduces the GSH/GSSG ratio, and ultimately enhances the sensitivity of HCC cells to OXA by upregulating ferroptosis [12]. Furthermore, studies have found that phosphorylation of LOXL3-S704 can inhibit ferroptosis by stabilizing the DHODH protein, leading to OXA resistance [13]. These findings collectively suggest that ferroptosis serves as a critical node in regulating the chemosensitivity to OXA. Based on this, exploring whether SIRT3 affects the sensitivity of HCC to oxaliplatin by modulating ferroptosis has become a key scientific question with significant potential clinical importance.

SIRT3 (Sirtuin 3) is a mitochondrial deacetylase belonging to the Sirtuin family proteins. Through NAD+ -dependent deacetylation, SIRT3 regulates the acetylation levels of multiple proteins, modulating various mitochondrial functions including cell metabolism, oxidative stress response, and apoptosis, exerting a dual role in cancer initiation and progression [14]. The process of oxidative stress is often closely related to ferroptosis, and mitochondrial metabolism is also involved in the occurrence of ferroptosis [15]. Therefore, SIRT3 has also been reported to be involved in the development of multiple diseases by modulating ferroptosis. For example, in Intestinal ischemia-reperfusion (I/R), resveratrol reduces ferroptosis and improves I/R damage by activating SIRT3 [16]. In Glioblastoma (GBM) cells, SIRT3 promotes ROS accumulation in the mitochondria, triggering mitochondrial autophagy and thus making glioblastoma sensitive to ferroptosis [17]. Notably, ferroptosis is also considered an important target for tumor therapy [18]. However, it is unclear whether SIRT3-induced ferroptosis affects the sensitivity of HCC to oxaliplatin and the underlying mechanisms.

ER stress and cancer have mutual crosstalk and are considered a major focus in cancer research. ER stress is a protective stress response in cells that responds to ER dysfunction, involving the accumulation of unfolded or misfolded proteins and disruption of calcium ion balance. Cells attempt to restore normal ER function through the unfolded protein response (UPR). The UPR is mainly achieved through three signaling pathways: the IRE1α pathway, PERK pathway, and ATF6 pathway [19]. These three classic ER stress sensor pathways are regulated by BiP/GRP78 [20], [21]. Research indicates that sustained endoplasmic reticulum stress promotes HCC progression through specific UPR pathways. For instance, the activated IRE1α pathway recruits SEC63, which activates ACLY to drive metabolic reprogramming, maintaining ER homeostasis and cooperatively upregulating EMT-related factors like Snail1 to facilitate HCC metastasis [22].In our study, we found that GRP78 is upregulated in HCC and is a critical component in the mechanism influencing the chemotherapy sensitivity of HCC.