It is well established that ferroptosis is primarily induced by peroxidation of long-chain poly-unsaturated fatty acid (PUFA) through nonenzymatic oxidation by free radicals or enzymatic stimulation of lipoxygenase. Although there is emerging evidence that long-chain saturated fatty acid (SFA) might be implicated in ferroptosis, it remains unclear whether and how SFA participates in the process of ferroptosis. Using endogenous metabolites and genome-wide CRISPR screening, we have identified FAR1 as a critical factor for SFA-mediated ferroptosis. FAR1 catalyzes the reduction of C16 or C18 saturated fatty acid to fatty alcohol, which is required for the synthesis of alkyl-ether lipids and plasmalogens. Inactivation of FAR1 diminishes SFA-dependent ferroptosis. Furthermore, FAR1-mediated ferroptosis is dependent on peroxisome-driven ether phospholipid biosynthesis. Strikingly, TMEM189, a newly identified gene which introduces vinyl-ether double bond into alkyl-ether lipids to generate plasmalogens abrogates FAR1-alkyl-ether lipids axis induced ferroptosis. Our study reveals a new FAR1-ether lipids-TMEM189 axis dependent ferroptosis pathway and suggests TMEM189 as a promising druggable target for anticancer therapy.

Emerging evidence reveals that amino acid metabolism plays an important role in ferroptotic cell death. The conversion of methionine to cysteine is well known to protect tumour cells from ferroptosis upon cysteine starvation through transamination. However, whether amino acids‐produced metabolites participate in ferroptosis independent of the cysteine pathway is largely unknown. Here, the authors show that the tryptophan metabolites serotonin (5‐HT) and 3‐hydroxyanthranilic acid (3‐HA) remarkably facilitate tumour cells to escape from ferroptosis distinct from cysteine‐mediated ferroptosis inhibition. Mechanistically, both 5‐HT and 3‐HA act as potent radical trapping antioxidants (RTA) to eliminate lipid peroxidation, thereby inhibiting ferroptotic cell death. Monoamine oxidase A (MAOA) markedly abrogates the protective effect of 5‐HT via degrading 5‐HT. Deficiency of MAOA renders cancer cells resistant to ferroptosis upon 5‐HT treatment. Kynureninase (KYNU), which is essential for 3‐HA production, confers cells resistant to ferroptotic cell death, whereas 3‐hydroxyanthranilate 3,4‐dioxygenase (HAAO) significantly blocks 3‐HA mediated ferroptosis inhibition by consuming 3‐HA. In addition, the expression level of HAAO is positively correlated with lipid peroxidation and clinical outcome. Together, the findings demonstrate that tryptophan metabolism works as a new anti‐ferroptotic pathway to promote tumour growth, and targeting this pathway will be a promising therapeutic approach for cancer treatment.

Sohlh2 belongs to the superfamily of basic helix‐loop‐helix (bhlh) transcription factors. Aberrant expression of bhlh transcription factors has been shown to be associated with multiple tumorigenesis. We previously identified that sohlh2 functioned as a tumor suppressor in ovarian cancer. Here, we examined the expression levels of sohlh2 in human breast cancer and its potential role in disease pathogenesis. The results of sohlh2 immunohistochemistry (IHC) and Western blot analysis demonstrated the decreased sohlh2 expression in breast cancer specimens as compared to adjacent noncancerous tissues. Through in vitro MTT, BrdU, colony formation and cell cycle assays and in vivo tumor xenograft studies, we showed that forced expression of sohlh2 led to a significant reduction in proliferation due to G1 arrest in vitro and tumorigenesis in nude mice. Conversely, silencing of sohlh2 enhanced breast cancer cell proliferation. Furthermore, we confirmed that sohlh2 inhibited breast cancer cell proliferation by suppressing the Wnt/β‐catenin signaling pathway. APC was the direct target of sohlh2, and mediated the inhibitory activities of sohlh2 on Wnt/β‐catenin signaling pathway. Thus, our data indicate that sohlh2 likely functions as a tumor suppressor in breast cancer that is mediated by repressing Wnt/β‐catenin signaling pathway via upregulation of APC expression.

Glioblastoma (GBM) is the most aggressive and highly invasive type of astrocytic tumors. Despite advances in diagnosis and therapy, the prognosis and survival time remain poor. Identifying key mediators of tumor cell proliferation, migration, and invasion is crucial to the development of new and more effective therapies. In this paper, we report the novel role of Spermatogenesis- and oogenesis- specific basic helix-loop-helix transcription factor1 (Sohlh1) in the inhibition of Wnt/β-catenin signaling and aggressive behaviors in GBM cells. Immunohistochemistry was performed to examine the expression of Sohlh1 and related proteins in astrocytomas. Human glioblastoma U87 and U251 cellswere transfected with appropriate plasmids and/or siRNAs to evaluate their functions on cell proliferation, migration, and invasion. Western blot and TOPflash luciferase assay were used to determine the involvement of Wnt/β-catenin signaling pathway in Sohlh1-mediated cellular activities in glioblastomas. We observed that Sohlh1 was downregulated in astrocytomas. The reduction in Sohlh1 expression was inversely correlated with the degree of malignancy in astrocytomas. In GBM cell lines, cellular proliferation, migration, and invasion were significantly enhanced after Sohlh1 knockdown, but significantly inhibited after Sohlh1 overexpression. These functional effects of Sohlh1 were achieved by upregulating GSK3β and inhibiting Wnt/β-catenin signaling. Our findings provide novel mechanistic insights of Sohlh1 in malignant progression of astrocytomas, suggesting that the level of Sohlh1 expression may be a predictor of astrocytoma behavior and further, Sohlh1 may serve as a potential therapeutic target for GBM.

Epithelial ovarian cancer (EOC) is the most common and deadly ovarian cancer. Most of the patients have abdominal/pelvic invasion and metastasis at the time of diagnosis, but the underlying mechanism remains unclear. Insufficiency of blood perfusion and diffusion within most solid tumors can lead to a hypoxic tumor microenvironment and promotes tumor malignancy. In the present study, we detected the role of the spermatogenesis- and oogenesis-specific basic helix-loop-helix (bHLH) transcription factor 2 (sohlh2) on migration, invasion and epithelial-mesenchymal transition (EMT) of EOC cell lines under hypoxia in vitro. We also investigated the possible mechanism underlying it. The results showed that sohlh2 inhibited the migration, invasion and EMT of EOC cells and might function through suppression of the hypoxia-inducible factor 1α (HIF1α)/carbonic anhydrase 9 (CA9) signaling pathway. Our results may open a new avenue for the further development of diagnostic tools and novel therapeutics that will benefit EOC patients.