Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

Abstract

Flavonoids are a class of bioactive phytochemicals containing a core 2-phenylchromone skeleton and are widely found in fruits, vegetables, and herbs. Such natural compounds have gained significant attention due to their various health benefits. Ferroptosis is a recently discovered unique iron-dependent mode of cell death. Unlike traditional regulated cell death (RCD), ferroptosis is associated with excessive lipid peroxidation on cellular membranes. Accumulating evidence suggests that this form of RCD is involved in a variety of physiological and pathological processes. Notably, multiple flavonoids have been shown to be effective in preventing and treating diverse human diseases by regulating ferroptosis. In this review, we introduce the key molecular mechanisms of ferroptosis, including iron metabolism, lipid metabolism, and several major antioxidant systems. Additionally, we summarize the promising flavonoids targeting ferroptosis, which provides novel ideas for the management of diseases such as cancer, acute liver injury, neurodegenerative diseases, and ischemia/reperfusion (I/R) injury.

Ferroptosis in Liver Disease: Natural Active Compounds and Therapeutic Implications

“…Furthermore, the existing studies on NAC for treating liver disease by regulating ferroptosis were mainly carried out on animal or cell in vitro, and molecular mechanisms underlying the therapeutic effects of these NAC require further investigation. For future clinical trials, appropriate drug dosage, efficient delivery methods, and safety evaluation will be the main issues to be addressed [ 14 ]. It is also worth exploring whether combining multiple NAC can achieve better efficacy.…”

“…NAC, including TCM, have become an important source for the development of drugs targeting ferroptosis due to their high therapeutic potential and low toxicity. Among them, various flavonoids and terpenoids have been reported to exert certain curative effects on liver disease via targeting ferroptosis [ 13 , 14 ]. Here, we summarize the therapeutic impact of newly discovered NAC on treating main liver disease and the potential mechanisms of regulating ferroptosis ( Figure 3 ).…”

“…As expected, more and more NAC are useful for direct or adjuvant liver disease treatment through ferroptosis regulation. Many NAC based on traditional Chinese medicine (TCM), such as baicalein, quercetin, and curcumin, are widely present in nature, even in our food, and are characterized by multi-target, structural stability, easy availability, and minimal negative effects [ 13 , 14 ]. Given the lack of a comprehensive overview of advances in using NAC to treat liver disease by targeting ferroptosis, we provide a systemic summary of the therapeutic actions and relevant molecular mechanisms of NAC in the improvement of major ferroptosis-related liver disease and further explore the clinical significance and potential issues.…”

Cloning, Expression, and Functional Characterization of Two Highly Efficient Flavonoid-di-O-glycosyltransferases ZmUGT84A1 and ZmUGT84A2 from Maize (Zea mays L.)

“…Flavonoids are a group of polyphenolic natural products ubiquitous in plants and exhibit a wide range of biological activities . Notably, numerous studies showed that flavonoids can improve human health by providing benefits such as antioxidation, anti-inflammation, anticancer, and antidiabetic activities. , Our previous study indicated that the C -glycoside flavone isoorientin can reduce Alzheimer′s disease-related markers in double transgenic APP/PS1 mice. , Plants are a natural source of flavonoid glycosides, but large-scale production of these compounds by plant extraction is cumbersome and inefficient, which has largely limited the exploration of their activities.…”

Myricetin Induces Ferroptosis and Inhibits Gastric Cancer Progression by Targeting NOX4

“…Furthermore, myricetin can regulate the production of ROS in an oxidase-dependent manner. − The generation of ROS is critical for lipid peroxidation and the onset of ferroptosis . Multiple flavonoids have demonstrated a correlation with ferroptosis and lipid peroxidation in cancer cells . The effects of myricetin on cancer may extend beyond its role in promoting apoptosis.…”