HO-1 Contributes to Luteolin-Triggered Ferroptosis in Clear Cell Renal Cell Carcinoma via Increasing the Labile Iron Pool and Promoting Lipid Peroxidation

Abstract

Ferroptosis, a novel form of regulated cell death characterized by disrupted iron metabolism and the accumulation of lipid peroxides, has exhibited enormous potential in the therapy of cancer particularly clear cell renal cell carcinoma (ccRCC). Luteolin (Lut), a natural flavonoid widely existing in various fruits and vegetables, has been proven to exert potent anticancer activity in vitro and in vivo. However, previous studies on the anticancer mechanism of Lut have been shown in apoptosis but not ferroptosis. In the present study, we identified that Lut substantially inhibited the survival of ccRCC in vitro and in vivo, and this phenomenon was accompanied by excessively increased intracellular Fe2+ and abnormal depletion of GSH. In addition, Lut induced the imbalance of mitochondrial membrane potential, classical morphological alterations of mitochondrial ferroptosis, generation of ROS, and occurrence of lipid peroxidation in an iron-dependent manner in ccRCC cells. However, these alterations induced by Lut could be reversed to some extent by the iron ion chelator deferiprone or the ferroptosis inhibitor ferrostatin-1, indicating that ccRCC cells treated with Lut underwent ferroptosis. Mechanistically, molecular docking further established that Lut probably promoted the heme degradation and accumulation of labile iron pool (LIP) by excessively upregulating the HO-1 expression, which led to the Fenton reaction, GSH depletion, and lipid peroxidation in ccRCC, whereas blocking this signaling pathway evidently rescued the Lut-induced cell death of ccRCC by inhibiting ferroptosis. Altogether, the current study shows that the natural compound monomer Lut exerted anticancer efficacy by excessively upregulating HO-1 expression and activating LIP to trigger ferroptosis in ccRCC and could be a promising and potent drug candidate for ccRCC treatment.

Heme Oxygenase Modulation Drives Ferroptosis in TNBC Cells

“…HO-1 overexpression has been demonstrated as a mechanism of resistance and malignancy progression in cancer cells; however, it has been demonstrated that low levels of HO-1 are associated with an increased risk of metastasis in oral and tongue squamous cell carcinoma, together with a significant presence of undifferentiated cells [ 44 ]. Additionally, data analysis by Han et al showed that low expression levels of HO-1 in renal carcinoma predicted poor prognosis, which might be improved by activating ferroptosis through the induction of HO-1 [ 45 ]. Furthermore, overexpression of HO-1 in prostate cancer cells resulted in markedly reduced cell proliferation and migration [ 46 ].…”

Ferroptosis and its role in skeletal muscle diseases

“…Meanwhile, this activity dependent increase of ROS will induce lipid peroxidation of cell membrane and damage the healthy tissue, thus aggravating muscle fatigue during strenuous exercise (Dillard et al, 1978;Alessio et al, 1988). Therefore, ferroptosis may be a new type of cell death that participates in the physiological and pathological process of EEIF except apoptosis (Sun Y. et al, 2016;Liu S. et al, 2022). Excitingly, a recent report explored the relationship between ferroptosis and EEIF (Xiao et al, 2022).…”

“…Therefore, the maintenance of systemic iron homeostasis requires the maintenance of a normal heme metabolism. The up-regulation of heme oxygenase 1 (HO-1), a crucial enzyme that degrades heme to liberate iron, can participate in ferroptosis induction by increasing intracellular iron levels ( Tenhunen et al, 1968 ; Han et al, 2022 ). HO-1 inhibitor zinc protoporphyrin IX was discovered to counteract erastin-induced ferroptosis in HT-1080 fibrosarcoma cells ( Kwon et al, 2015 ).…”

Ferroptosis—A New Dawn in the Treatment of Organ Ischemia–Reperfusion Injury

“…By reacting with polyunsaturated lipids (LH), hydroxyl radicals generate lipid peroxyl radicals, and arachidonate lipoxygenases (ALOXs) can also oxidize LH into hydroperoxide (LOOH), which is then converted into lipid peroxyl radical by Fenton reaction. Eventually, the lipid peroxyl radicals initiate and facilitate lipid peroxidation [ 15 , 16 ]. Moreover, iron can enhance the activity of lipoxygenases (ALOXs) and cytochrome P450 oxidoreductase (POR), which are metabolic enzymes associated with phospholipid peroxidation ( Figure 2 ).…”