Tryptophan Metabolism Acts as a New Anti‐Ferroptotic Pathway to Mediate Tumor Growth

Abstract

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.

Cholesterol mediated ferroptosis suppression reveals essential roles of Coenzyme Q and squalene

“…Alteration of metabolism has been increasingly linked to change of cell susceptibility to cell death. Multiple lines of evidence support this notion in the lipid peroxidation associated cell death, known as ferroptosis 16,19,29 . Among various metabolic cues that regulate ferroptosis, lipid metabolism, in particular, fatty acid metabolism has been most intensively investigated.…”

Identification of a targeted ACSL4 inhibitor to treat ferroptosis-related diseases

“…However, iron is an essential element for many fundamental physiological activities, and chelation iron by deferoxamine may increase the risk of iron imbalance (35,36). Vitamin K, serotonin (5-hydroxytryptamine), 3-hydroxyanthranilic acid, Fer-1, and liproxstatin-1 were found to inhibit ferroptosis by acting as potent RTAs (37)(38)(39), suggesting that these compounds may have a wide range of antioxidant effects. In addition, itaconate, quercetin, and resveratrol have been found to inhibit ferroptosis via defense against oxidative stress (40,41).…”

Discovering KYNU as a feature gene in hidradenitis suppurativa

“…KYNU is widely expressed in nearly all organs of the body, with particularly elevated levels observed in the liver, urinary bladder, and appendix. 50 KYNU is involved in various inflammatory skin diseases, [51][52][53][54][55] cardiovascular diseases, 56 inflammatory bowel disease, 57,58 and several types of cancers, [59][60][61][62][63] exerting its effects through diverse pathways. While previous studies have indicated abnormalities in tryptophan metabolism within HS lesions, 18 there is currently a scarcity of research confirming the distinctive expression pattern of KYNU specifically in HS.…”