Ferritinophagy, a form of autophagy, is also an important part of ferroptosis, a type of regulated cell death resulting from abnormal iron metabolism involving the production of reactive oxygen species. As ferroptosis, autophagy and cancer have been revealed, ferritinophagy has attracted increasing attention in cancer development. In this review, we discuss the latest research progress on ferroptosis, autophagy-associated ferroptosis led by ferritinophagy, the regulators of ferritinophagy and promising cancer treatments that target ferritinophagy. Ferritinophagy is at the intersection of ferroptosis and autophagy and plays a significant role in cancer development. The discussed studies provide new insights into the mechanisms of ferritinophagy and promising related treatments for cancer.

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Ferroptosis is an iron-dependent nonapoptotic regulated cell death modality characterized by lethal levels of lipid peroxide accumulation and disrupted antioxidant systems. An increasing number of studies have revealed correlations between ferroptosis and the pathophysiology and treatment of cancer. Given the intricate involvement of mitochondria in ferroptosis, as suggested by previous studies, here, we review advances in understanding the roles of mitochondrial quality control and mitochondrial metabolism (including the roles of the TCA cycle, reactive oxygen species, iron metabolism, and lipid metabolism) in cancer-related ferroptosis and outline the molecular mechanism and clinical translation of mitochondria-related ferroptosis in cancer treatment. with the aim of promoting the precise utilization and prevention of ferroptosis in cancer therapeutics.

Bladder cancer is a common tumor that impacts the urinary system and marked by a significant fatality rate and an unfavorable prognosis. Promising antineoplastic properties are exhibited by brusatol, which is obtained from the dried ripe fruit of Brucea javanica. The present study aimed to evaluate the influence of brusatol on the progression of bladder cancer and uncover the molecular mechanism involved. We used Cell Counting Kit-8, colony formation and EdU assays to detect cell numbers, viability and proliferation. We used transwell migration assay to detect cell migration ability. The mechanism of brusatol inhibition of bladder cancer proliferation was studied by flow cytometry and western blotting. It was revealed that brusatol could reduce the viability and proliferation of T24 and 5637 cells. The transwell migration assay revealed that brusatol was able to attenuate the migration of T24 and 5637 cells. We found that treatment with brusatol increased the levels of reactive oxygen species, malondialdehyde and Fe²⁺, thereby further promoting ferroptosis in T24 and 5637 cells. In addition, treatment with RSL3 (an agonistor of ferroptosis) ferrostatin-1 (a selective inhibitor of ferroptosis) enhanced or reversed the brusatol-induced inhibition. In vivo, treatment with brusatol significantly suppressed the tumor growth in nude mice. Mechanistically, brusatol induced ferroptosis by upregulating the expression of ChaC glutathione-specific gamma-glutamylcyclotransferase (Chac1) and decreasing the expression of SLC7A11 and Nrf2 in T24 and 5637 cells. To summarize, the findings of this research demonstrated that brusatol hindered the growth of bladder cancer and triggered ferroptosis via the Chac1/Nrf2/SLC7A11 pathway.

Background: Glioma is the most common and aggressive primary brain tumor in adults. Proteasome 26S subunit, non-ATPase 12 (PSMD12), an important subunit in the 26S proteasome, is known to be involved in the growth and apoptosis of breast cancer cells. However, its exact function and underlying molecular mechanisms in glioma remain unknown. Methods: PSMD12 expression was detected in glioma tissue specimens by immunohistochemistry (IHC) and TCGA database. Overexpression and down-regulation of PSMD12 and Nrf2 were induced in glioma cell lines, and CCK-8 and Transwell assays were used to detect cell proliferation and invasion evaluation, respectively. Xenograft model was used to observe the effect of knockdown of PSMD12 on tumor growth. Immunohistochemical assays and TCGA database were conducted to reveal the relationships between PSMD12 expression and Nrf2. Finally, Western blot and related biological function experiments were used to explore the mechanism of PSMD12 regulating the glioma progression and Nrf2. Results: We revealed that PSMD12 is upregulated in glioma, especially in high-grade glioma, by analyzing bioinformatics data and clinical specimens. PSMD12 upregulation was associated with poor prognosis in glioma patients. Knockdown of PSMD12 inhibited the growth of glioma cells in vitro and in vivo and decreased their invasion ability, whereas PSMD12 overexpression had the opposite effect. Mechanistic analysis revealed that PSMD12 increased the expression of nuclear factor E2-related factor 2 (Nrf2), which functions as a tumor promoter in the development of glioma. Similar to PSMD12, Nrf2, which exhibited a strong positive correlation with PSMD12, was abnormally elevated in glioma tissues and contributed to worse overall survival (OS). Nrf2 overexpression reversed the inhibitory effects induced by PSMD12 knockdown. Finally, PSMD12 enhanced the proliferation and invasion of glioma cells via Akt signaling-mediated Nrf2 expression. Conclusions: These results suggest that PSMD12 is considered to be a crucial regulator of the development and progression of glioma and may serve as a potential biomarker or therapeutic target for the treatment of glioma.

Breast cancer (BC) is the most common malignancy among women. Mesenteric estrogen-dependent adipogenesis gene (MEDAG) was first reported as a novel adipogenic gene, and its involvement and mechanism in visceral adiposity were analyzed. However, the role of MEDAG in BC is unclear. The biological roles and corresponding mechanisms were investigated in vitro and in vivo. We found that MEDAG was highly expressed in BC samples and that a high MEDAG expression was correlated with clinicopathological characteristics and poor survival in BC patients. MEDAG knockdown inhibited cell proliferation, invasion, and migration; triggered epithelial-to-mesenchymal transition (EMT); and enhanced epirubicin sensitivity in vitro. The opposite results were observed in MEDAG-overexpressing cells. The inhibition of MEDAG suppressed tumor growth and metastasis in vivo. Mechanistically, MEDAG knockdown led to decreased phosphorylation levels of AKT, increased levels of p-AMPK, and reduced levels of p-mTOR, while the overexpression of MEDAG had the opposite effects. Moreover, the activation of p-AKT and inhibition of p-AMPK restored the effect of MEDAG on EMT and chemosensitivity in BC cell lines, indicating that MEDAG functions as an oncogene by regulating the AKT/AMPK/mTOR pathway. MEDAG regulates BC progression and EMT via the AKT/AMPK/mTOR pathway and reduces chemosensitivity in BC cells. Therefore, MEDAG is a promising target for BC.