Rhamnazin Inhibits Hepatocellular Carcinoma Cell Aggressiveness in Vitro via Glutathione Peroxidase 4-Dependent Ferroptosis

Abstract

Ferroptosis, a newly recognized type of programmed cell death, is characterized by lipid peroxidation and implicated in multiple pathophysiological processes.Ferroptosis agonists are attracting tremendous attention for the clinical management of malignancy. We uncovered that rhamnazin exerted its anticancer property via reducing cell proliferation and invasion in hepatocellular carcinoma (HCC) cells. The ferroptosis inhibitor ferrostatin-1 (Fer-1) partially A c c e p t e d M a n u s c r i p t 2 reversed rhamnazin-triggered cell proliferation inhibition, indicating that ferroptosis contributed to the inhibitory potency of rhamnazin. Further characterization corroborated that exposure with rhamnazin, reactive oxygen species (ROS) accumulation and lipid peroxidation, and iron content were elevated in HCC cells. Mechanistically, we demonstrated that glutathione peroxidase 4 (GPX4) was involved in rhamnazin-initiated ferroptotic cell death. Overexpression of GPX4 weakened HCC cell ferroptosis caused by rhamnazin.Collectively, these results strongly suggest that rhamnazin exerts a ferroptoticinduce role in HCC cells by inhibiting GPX4 expression.

Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

“…Icariside II, a flavonol glycoside derived from Epimedium koreanum , could suppress the expression of GPX4 via up-regulating miR-324-3p and thus promoted ferroptosis in renal cell carcinoma cells, indicating that icariside II might be used as an adjuvant therapy for renal cancer . Of note, several flavonols, including kaempferol, icariin, and rhamnazin, also regulated cell sensitivity to ferroptosis by targeting GPX4. − These data reveal that the GPX4-GSH system is the primary molecular mechanism through which flavonols perform their pharmacological functions.…”

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy

“…A pivotal revelation is Rhamnazin's reduction of GPX4 protein expression, a key player in ferroptosis. Notably, elevating GPX4 levels counteracts Rhamnazin's suppressive impact on cell proliferation and colony formation, signifying the centrality of GPX4 in Rhamnazin‐induced ferroptosis in HCC (Mei et al, 2022).…”

Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance

“…[ 61 ] Abnormal methylation of the promoter region of Protocadherin Beta 14 (PCDHB14) leads to its reduced expression in HCC cells, [ 62 ] which can inhibit cell proliferation and induce ferroptosis in HCC cells, while rhamnolipids suppressed cell proliferation and aggression, and rhamnetin induced ferroptosis by inhibiting GPX4 expression. [ 63 ] Moreover, HULC promoted HCC cell proliferation and metastasis, inhibited ferroptosis by binding to miR‐3200‐5b and targeting Activating transcription factor 4, and YAP‐ TEA Domain enhanced ferroptosis by targeting Arachidonate lipoxygenase 3, effectively increasing their vulnerability to ferritin‐mediated cell death. [ 64 ]…”