Targeting SOX13 to Overcome Iron Death Resistance in Gastric Cancer

Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of cancer-related deaths in the world. Despite significant progress in gastric cancer management, the prognosis of patients with advanced gastric cancer remains poor. Cisplatin-based chemotherapy is still the first-line adjuvant or neoadjuvant treatment for advanced gastric cancer, but understanding chemotherapy resistance remains a barrier to clinical efficacy. Cancer immunotherapy, including immune checkpoint inhibitors, has become an effective treatment for various types of cancer. However, due to drug resistance, only a small percentage of gastric cancer patients (about 15%) respond to immunotherapy. Therefore, more research is needed to elucidate the mechanisms of chemotherapy and immune resistance.

Iron death is considered a common nonapoptotic cell death pathway, ultimately leading to excessive lipid peroxidation caused by metabolic abnormalities. Iron death is related to the efficacy of various anti-cancer therapies, including radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Erastin is a strong inhibitor of system Xc -, and RSL3 is a typical GPX4 inhibitor. This study investigated different endogenous iron death inhibition systems. Therefore, researchers chose them for subsequent experiments. Metabolic reprogramming has been recognized as one of the hallmarks of cancer and maybe a treatable strategy to overcome drug resistance.

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In this work, based on previous research on cancer metabolism, researchers proposed a potential metabolic mechanism that confers resistance to ferroptosis, chemotherapy, and immunotherapy. The researchers demonstrated that targeting SOX13/SCAF1 inhibits the assembly of respiratory chain supercomplexes (SCs) to overcome iron-mediated resistance to gastric cancer anticancer therapy.

Recently, researchers from the First Affiliated Hospital of Wannan Medical College published an article in the Nat Commun journal titled "Targeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer". This study demonstrates that SOX13 directly targets SCAF1 and may inhibit ferroptosis by inducing the production of NADPH, which is a potential chemotherapy-sensitive treatment strategy for advanced gastric cancer patients.

Drug resistance is a bottleneck in the treatment of advanced gastric cancer (GC). Iron-dependent cell death is a form of non-apoptotic cell death that is associated with the efficacy of anti-cancer therapy, and further investigation is needed to clarify potential mechanisms.

The researchers constructed an anti-iron oxide GC cell line and identified the mRNA imbalance between the iron-resistant apoptotic cell line and the parent cell line. Manipulate the expression of SOX13/SCAF1 in GC cell lines and perform relevant biological and molecular analysis. Screening potential inhibitors of SOX13 through molecular docking and computational screening. Researchers have found that SOX13 promotes protein remodeling of electron transfer chain (ETC) complexes by directly activating SCAF1. This leads to increased assembly of supercomplexes (SCs), mitochondrial respiration, mitochondrial energetics, as well as chemical and immune resistance. Zanamivir restores its anti-iron toxicity phenotype by directly targeting SOX13 and promoting trim25-mediated ubiquitination and SOX13 degradation. This study indicates that SOX13/SCAF1 plays an important role in ferrophilic resistance, and targeting SOX13 with zanamivir has therapeutic potential.

In summary, this study reveals a potential metabolic mechanism that endows gastric cancer with resistance to iron death and iron death mediated therapies, including cisplatin and immunotherapy. Research has found that SOX13 promotes protein remodeling of electron transfer chain (ETC) complexes by deactivating the expression of SCAF1. This leads to increased assembly of SCs, mitochondrial respiration, mitochondrial energetics, and drug resistance. Inhibiting SOX13/SCAF1 can restore the sensitivity of iron-resistant antagonistic GC cell lines and reverse their chemotherapy effect on iron-resistant GC cell lines. Researchers have demonstrated that SOX13 directly targets SCAF1 and may inhibit ferroptosis by inducing the production of NADPH, which is a potential therapeutic strategy that can increase chemotherapy sensitivity in advanced gastric cancer patients. However, the exact molecular mechanism needs further investigation.

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Reference Hui Yang et al. Targeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer. Nat Commun. 2024 May 20;15(1):4296. doi: 10.1038/s41467-024-48307-z.