Ferroptosis and Traditional Chinese Medicine for Type 2 Diabetes Mellitus

Figures & data

Figure 1 Mechanism of ferroptosis occurrence. This figure was created with Figdraw (www.figdraw.com).

Figure 2 Regulation of ferroptosis suppressing pathways and suppressors. This figure was created with Figdraw (www.figdraw.com). Cytoplasmically located GPX4, mitochondrially located GPX4 and DHODH, plasma membrane located FSP1, and GCH1 (“?” indicates that the exact subcellular localization is unknown), together mediating the ferroptosis defense mechanism.

Table 1 The Role of Ferroptosis in the Therapeutic Use of TCM for T2DM and Its Related Complications

TCM or its Active Ingredients	Disease	Model	Mechanism of Ferroptosis Regulation	Functional Role
Curcumin and (-)- Epigallocatechin-3-Gallate^Citation63	T2DM	MIN6 cells	Reduced intracellular MDA levels and iron accumulation, and attenuated the reduction of GSH and GPX4 protein levels	Inhibit ferroptosis
Grape seed procyanidin^Citation64,Citation65	T2DM	SD rat (STZ induced), MIN6 cells	Activated Nrf2 signaling pathway in MIN6 cells, reduced MDA and ROS levels, upregulated SLC7A11 and GPX4 protein expression; reduced MDA and iron content, upregulated GSH and SOD levels in T2DM rat pancreatic tissues	Inhibit ferroptosis
Quercetin^Citation66	T2DM	C57BL/6J mice (STZ induced), INS-1 cells	Lowered the iron level, upregulated GSH and GPX4 expression	Inhibit ferroptosis
Cryptochlorogenic Acid^Citation67	T2DM	SD rat (STZ induced), INS-1 cells	Activated cystine/glutamate transporter system/GPX4/Nrf2, inhibited NCOA4	Inhibit ferroptosis
Sennoside A^Citation68	DKD	C57BL/6J mice (STZ induced)	Downregulated expression of Nrf2, HO-1 and PTGS2, increased GPX4 expression	Inhibit ferroptosis
Berberine^Citation69	DKD	MPC5 cells	Reduced ROS production, increased GSH levels, upregulated expression of Nrf2, HO-1, GPX4 and podocin, decreased PTGS2 and ACSL4 levels	Inhibit ferroptosis
Umbelliferone^Citation70	DKD	C57BLKS/J db/db mice, HK-2 cells	Upregulated Nrf2, GPX4 and HO-1 expression, downregulated ACSL4 expression, activated the Nrf2/HO-1 pathway	Inhibit ferroptosis
Platycodin D^Citation71	DKD	HK-2 cells	Upregulated GPX4, FTH-1 and SLC7A11 expression, downregulated ACSL4 and TRF1 expression	Inhibit ferroptosis
Resveratrol^Citation72	DCM	H9c2 cells	Upregulated expression of HSF1, GPX4 and SLC7A11, downregulated ACSL4 expression, reduced Fe2+ content	Inhibit ferroptosis
Gegen Qinlian Decoction^Citation73	DCM	C57BL/KsJ-db/db mice	Upregulated GPX4 and SLC7A11 expression, downregulated ACSL4 and PTGS2 expression, reduced MAD content	Inhibit ferroptosis
Sulforaphane^Citation74	DCM	AMPKa2-KO mice, in vitro DCM model	Upregulated ferritin and SLC7A11 levels, activated the AMPK/Nrf2 pathway	Inhibit ferroptosis
Astragaloside-IV^Citation75	DR	ARPE-19 cells	Increased expression of GPX4, GCLM and GCLC, inhibited miR-138-5p expression, increased Sirt1/Nrf2 activity and cellular antioxidant capacity	Inhibit ferroptosis

Abbreviations: AGEs, advanced glycation end-products; AMPK, AMP-activated protein kinase; DCM, diabetic cardiomyopathy; DKD, diabetic kidney disease; DR, diabetic retinopathy; FTH-1, ferritin heavy chain 1; GCLC, glutamate cysteine ligase catalytic subunit; GCLM, glutamate cysteine ligase; GPX4, glutathione peroxidase 4; GSH, glutathione; HO-1, heme oxygenase-1; NCOA4, nuclear receptor coactivator 4; Nrf2, nuclear factor erythroid 2-related factor 2; ROS, reactive oxygen species; Sirt1, silent information regulator 1; STZ, streptozotocin; TCM, traditional Chinese medicine; T2DM, type 2 diabetes mellitus.

Figure 3 Flow chart of the literature retrieval and screening process.

Figure 4 Mechanism in the treatment of T2DM and its complications with TCM by inhibiting ferroptosis. This figure was created with Figdraw (www.figdraw.com).

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