Ferroptosis, a form of iron-dependent cell death characterized by lipid peroxidation, has emerged as a promising strategy to overcome resistance to chemotherapy. This review explores the mechanisms of ferroptosis and its potential to reverse drug resistance in digestive system cancers. We summarize recent advances in understanding the GPX4-regulated pathway, iron metabolism, and lipid peroxidation as key drivers of ferroptosis. It also highlights the roles of tumor heterogeneity, tumor–stroma interactions, abnormal apoptosis, metabolic alterations, and the tumor microenvironment in drug resistance. Specific mechanisms of ferroptosis resistance in esophageal squamous cell carcinoma, gastric cancer, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, and colorectal cancer are discussed, along with strategies to induce ferroptosis to reverse drug resistance. Future research should focus on translating these findings into clinical applications through targeted therapies and combination treatments to improve patient outcomes.

The incidence and mortality rates of cancer are increasing every year worldwide but the survival rate of cancer patients is still unsatisfactory. Therefore, it is necessary to further elucidate the molecular mechanisms involved in tumor development and drug resistance to improve cancer cure or survival rates. In recent years, autophagy has become a hot topic in the field of oncology research, which plays a double-edged role in tumorigenesis, progression, and drug resistance. Meanwhile, long non-coding RNA (lncRNA) has also been shown to regulate autophagy, and the two-sided nature of autophagy determines the dual regulatory role of autophagy-related lncRNAs (ARlncRNAs). Therefore, ARlncRNAs can be effective therapeutic targets for various cancers. Furthermore, the high abundance and stability of ARlncRNAs in tumor tissues make them promising biomarkers. In this review, we summarized the roles and mechanisms of ARlncRNAs in tumor cell proliferation, apoptosis, migration, invasion, drug resistance, angiogenesis, radiation resistance, and immune regulation. In addition, we described the clinical significance of these ARlncRNAs, including as biomarkers/therapeutic targets and their association with clinical drugs.