Targeting mitochondrial damage and ER stress to inhibit ferroptosis in cadmium-induced nephrotoxicity

Abstract

This review highlights the pivotal roles of autophagy, ferroptosis, and endoplasmic reticulum (ER) stress in mediating cadmium (Cd)-induced nephrotoxicity. Cadmium exposure results in ER stress, which in turn activates major UPR pathways such as IRE1, ATF6, and PERK. By encouraging lipid peroxidation and suppressing cellular antioxidant defence, these mechanisms worsen ferroptosis and produce a feedback mechanism that increases cellular damage. There are two roles of autophagy in Cd-induced ferroptosis, which include its action in reducing cadmium-induced cytotoxicity by breaking down damaged components, and excessive autophagy, namely ferritinophagy, which promotes ferroptosis by iron dysregulation. The rise of mitochondrial ROS (MitoROS) caused by Cd-induced mitochondrial malfunction aids ferroptosis. This, in turn, causes ER stress and autophagy. This implies that focusing on mitochondrial health could be a useful treatment strategy. Effective treatment approaches include autophagy inhibitors like chloroquine, which have been shown to effectively reduce Cd-induced ferroptosis, and promising medicines that suppress ER stress, such as TUDCA. Desferrioxamine and other iron chelators effectively lower lipid peroxidation and iron dysregulation, therefore preventing ferroptotic cell death. Additionally, a multi-targeted treatment plan is suggested that targets iron metabolism, ER stress, and autophagy. In order to create tailored treatments for Cd-induced nephrotoxicity, this review emphasizes the need for additional study into the molecular pathways of Cd-induced ferroptosis, namely the ER stress-autophagy axis. The goal of future research should be to apply these mechanistic insights to clinical settings to enhance public health outcomes and create efficient therapies for renal failure brought on by cadmium toxicity.

Keywords: Autophagy inhibitors; Cadmium effects; Ferroptosis; Mitochondrial ROS; Nephrotoxicity; Renal Tubular Epithelial Cells.

Graphical abstract

Fig. 1

Renal tubular epithelial cells that have experienced ferroptosis brought on by the cadmium exposure disrupted cellular homeostasis as well as activation of autophagy mediated by endoplasmic reticulum stress. PGC-1α, also known as gamma coactivator 1-alpha, and FOXO3 (also known as Forkhead box O3).

Fig. 2

Antioxidant response to cadmium exposure. Cadmium triggers ROS production, activating SOD, GSH, and CAT. SOD converts superoxide to H₂O₂, which is then neutralized by GSH and CAT to reduce oxidative stress.

Fig. 3

Systemic effects of cadmium toxicity, highlighting inflammation and oxidative stress across multiple organs. Signs include immune cell infiltration, elevated cytokines, ROS accumulation, and cellular damage. Affected organs—such as the kidneys, liver, heart, vasculature, and skin—exhibit structural and functional impairments due to cadmium accumulation.

Fig. 4

Cadmium-induced damage in the proximal convoluted tubule (PCT) of the kidney, showing disrupted structure, cellular necrosis, and mitochondrial dysfunction, resulting in impaired reabsorption and nephrotoxicity.