Inhibitory effects of herbal monomers on ferroptosis in renal fibrosis: a review and mechanistic study

Abstract

Background and purpose: Renal fibrosis is a common characteristic of chronic kidney disease (CKD). Studies have confirmed the role of ferroptosis in the pathogenesis of various kidney diseases, making it a new research hotspot in the field of renal fibrosis. Monomers of Chinese herbal medicines (CHMs) can improve renal fibrosis by multi-target inhibition of ferroptosis. This review aimed to explore the roles and mechanisms of CHMs in renal fibrosis.

Methods: Using the keywords "ferroptosis", "chronic kidney disease", "renal fibrosis", "Chinese herbal medicine", "natural products", "bioactive components", and "herb", we conducted an extensive literature search of several databases, including PubMed, Web of Science, CNKI, and Wanfang database, to identify studies reporting the role of CHM monomers in inhibiting ferroptosis and improving renal fibrosis. The names of the plants covered in the review have been checked through MPNS (http://mpns.kew.org). All monomers of CHMs were identified in the Pharmacopoeia of the People's Republic of China.

Results: In total, 21 monomers of CHMs were identified in this study, most of which were flavonoids, followed by terpenoids and coumarins. This review showed that monomers of CHMs inhibited ferroptosis and improved renal fibrosis through multi-target mechanisms. They maintained iron homeostasis by acting on NCOA4 and Nrf2 to reduce ferritinophagy. They also inhibited lipid peroxidation and regulated the antioxidant system by modulating ACSL4, NOX4, Nrf2, FSP1, and GPX4 and inhibiting Smad3 to improve renal fibrosis.

Conclusion: Monomers of CHMs effectively inhibited ferroptosis and prevented renal fibrosis in various animal models and cell models of CKD. However, further in-depth studies with better designs are needed to identify the exact targets of monomers of CHMs and improve the treatment of renal fibrosis and CKD.

Keywords: Chinese herbal medicine; chronic kidney disease; ferroptosis; monomers; renal fibrosis.

FIGURE 1

Iron metabolism mechanism. Transferrin (TF), transferrin receptor 1 (TFR1), ferroportin 1 (FPN1), six-transmembrane epithelial antigen of the prostate 3 (STEAP3), divalent metal transporter 1 (DMT1), labile iron pool (LIP), reactive oxygen species (ROS), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), nuclear receptor coactivator 4 (NCOA4), nuclear factor erythroid 2-related factor 2 (Nrf2), NADPH oxidases (NOXs), lipoxygenase (LOX), cyclooxygenase (COX), polyunsaturated fatty acids (PUFAs), and phosphorylated Smad3 (p-Smad3).

FIGURE 2

Lipid peroxidation mechanism. Polyunsaturated fatty acids (PUFAs), acetyl-CoA carboxylase (ACC), acyl-CoA synthetase long-chain family member 4 (ACSL4), arachidonic acid (AA), adrenic acid (AdA), phosphatidylethanolamine (PE), lysophosphatidylcholine acyltransferase 3 (LPCAT3), PUFA-phospholipids (PUFA-PE), NADPH oxidases (NOXs), reactive oxygen species (ROS), lipoxygenases (LOXs), cyclooxygenases (COXs), lipid hydroperoxides (PUFA-OOH), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), AMP-activated protein kinase (AMPK), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE).

FIGURE 3

Oxidation system mechanism. Cystine/glutamate antiporter (System Xc⁻), glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), solute carrier family 3 member 2 (SLC3A2), glutathione (GSH), nuclear factor erythroid 2-related factor 2 (Nrf2), activating transcription factor 3 (ATF3), Mothers against decapentaplegic homolog 3 (Smad3), ferroptosis suppressor protein 1 (FSP1), coenzyme Q10 (CoQ10), ubiquinol (CoQ10H₂), nicotinamide adenine dinucleotide phosphate (NADPH).

FIGURE 4

Schematic overview of renal fibrosis, ferroptosis, and TGF-β/Smad pathway activation in chronic kidney disease (CKD). This figure depicts the pathological mechanisms underlying renal fibrosis in CKD associated with ferroptosis. Tubular injury activates Fe²⁺ accumulation, leading to the Fenton reaction that generates reactive oxygen species (ROS). Increased ROS levels promote lipid peroxidation, which is inhibited by SLC7A11 and GPX4. Concurrently, the TGF-β1/Smad3 signaling, which is activated by tubular injury, enhances ROS production by triggering NOXs/NOX4 and promotes epithelial-mesenchymal transition (EMT). This complex pathway leads to myofibroblast activation through ferroptosis, characterized by α-SMA activation and enhanced production of ECM components (e.g., COLI, COLIV and FN), exacerbating kidney fibrosis.

FIGURE 5

Monomer mechanism and target. Transferrin (TF), transferrin receptor 1 (TFR1), six-transmembrane epithelial antigen of the prostate 3 (STEAP3), divalent metal transporter 1 (DMT1), labile iron pool (LIP), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), nuclear receptor coactivator 4 (NCOA4), Polyunsaturated fatty acids (PUFAs), acetyl-CoA carboxylase (ACC), acyl-CoA synthetase long-chain family member 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), PUFA-phospholipids (PUFA-PE), lipid hydroperoxides (PUFA-OOH), Cystine/glutamate antiporter (System Xc⁻), glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), solute carrier family 3 member 2 (SLC3A2), glutathione (GSH), nuclear factor erythroid 2-related factor 2 (Nrf2) and ferroptosis suppressor protein 1 (FSP1).