AKI, also known as acute renal failure, is defined as an abrupt (within hours) decrease in kidney function, ranging from minor loss of kidney function to complete kidney failure ^[1][2]. AKI is common in patients who are critically ill and already in the hospital especially elderly patients in intensive care units. AKI diagnostic is based on the acute reduction in glomerular filtration rate (GFR) with time intervals ^[1][2]. AKI can be caused by a reduction in blood flow, direct injury to the kidneys, and urinary tract block ^[2][3]. Signs and symptoms of AKI differ depending on the cause, such as not enough urine, swelling in legs, ankles, or around the eyes, and fatigue or tiredness. Generally, vasoconstriction, oxidative stress, apoptosis, inflammation, and hypoxia are the major pathogenic mechanisms of AKI ^[3][38]. In the past, apoptosis was considered as the main regulated cell death in various models of ischemic injury. However, later discoveries suggested that ferroptosis might be a major driver of AKI induced by either ischemia–reperfusion injury (IRI) or oxalate crystal, which is directly involved in the synchronized necrosis of renal tubules ^[4][39]. IRI is the main cause of AKI in patients who have undergone cardiac surgery in the clinic. It has been reported that low levels of intraoperative iron-binding proteins, such as serum ferritin, and higher transferrin saturation may reflect an impaired ability to rapidly process catalytic iron released during extracorporeal circulation and lead to kidney damage ^[5][40].

Glutathione/glutathione peroxidase 4(GPX4) is the key regulator of ferroptosis that can be degraded by chaperone-mediated autophagy (CMA). It has been shown that the inhibition of CMA can reduce ferroptosis by stabilizing GPX4 ^[6][41]. Legumain is conserved as asparaginyl endopeptidase that is highly expressed in proximal tubular cells and promotes chaperone-mediated autophagy of GPX4 ^[7][42]. It has been reported that legumain deficiency could ameliorate tubular cell ferroptosis through stabilizing GPX4 in an AKI animal model induced by IRI or nephrotoxic folic acid. In another, AKI model induced by cisplatin, vitamin D receptor activation protected against cisplatin-induced renal injury by inhibiting ferroptosis partly via trans-regulation of GPX4 ^[8][43]. In addition, the incidence and mortality in spontaneous AKI were significantly increased in GPX4 knocked mice ^[9][30]. The survival of the GPX4-deficient mice could be extended by approximately 35% by the clearance of lipid peroxides in vivo ^[9][30]. These findings suggest that inhibition of GPX4 may play an important role in ferroptosis-associated kidney injury.

Due to the role of iron in mediating the production of reactive oxygen species and enzyme activity in lipid peroxidation, iron metabolism is thought to be one of the central mediators of ferroptosis. The regulation of iron metabolism can suppress inflammation, oxidative stress, and cell damage caused by iron overload and iron disorders. Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in the degradation of heme, which is precursive to hemoglobin and constitutes 95% of functional iron in the human body. Heme can be degraded into bilirubin, CO, and Fe²⁺. Upregulation of HO-1 enhances the degradation of heme and the synthesis of ferritin, altering the intracellular iron distribution ^[10][44]. As a dual regulator in iron and ROS homeostasis, HO-1 is suggested to serve a dominant role in ferroptosis ^[11][45]. The expression of HO-1 is upregulated in response to oxidant stress in proximal tubular cells (PTCs) in vitro, which exerts cytoprotective and anti-inflammatory effects ^[12][13][46,47]. Knockdown HO-1 are highly sensitive to erastin- and RSL3-induced ferroptosis, whereas treatment with ferrostain-1 (Fer-1) attenuates cellular stress and death in PTCs undergoing ferroptosis in vitro. Moreover, the protective role of HO-1 has also been demonstrated in several animal models of AKI ^{[14][15][16][17]}[48,49,50,51]. For example, in the AKI model induced by rhabdomyolysis, induction of HO-1 before injury has resulted in a significant attenuation of structural damage, prevention of kidney failure, and decreasing mortality. In the AKI model induced by cisplatin, HO-1 (^−/−) mice developed more severe renal failure compared with HO-1 (^+/+) mice. These findings suggested that HO-1 induction may play an important role in conferring protection on renal cells from oxidative damage and has an anti-ferroptosis effect in renal epithelial cells.

Rhabdomyolysis accounts for 15% of all causes of AKI and the accumulation of myoglobin in the kidney is the key mechanism leading to kidney damage ^[18][52]. Myoglobin can be degraded in the kidney, resulting in the release of iron, which participates in the production of oxidizing substances through the catalytic action of the Fenton reaction and the induction of lipid peroxidation in proximal tubular epithelial cells in the AKI animal model induced by rhabdomyolysis ^[19][53]. Treatment with iron chelator deferoxamine could alleviate renal injury induced by rhabdomyolysis in vivo and prevent cytotoxicity in vitro ^[20][21][54,55]. These findings suggested that iron-dependent ferroptosis may play an important role in rhabdomyolysis-induced renal injury. Hepcidin, a major regulator of iron homeostasis that prevents iron export from cells by inducing the degradation of the iron export protein, ferroportin ^[22][56]. Ferroportin is located at the basolateral membrane of the proximal tubules in the kidneys ^[23][57]. The expression of ferroportin is increased in response to export hepatosplenic iron, which results in the alterations of systemic iron homeostasis, including hepatosplenic iron depletion, and increased serum and kidney nonheme iron levels in the renal IRI animal model ^[24][58]. Knockout of ferroportin (^−/−) increased the expression of FTH1, resulting in the chelation of iron and the inhibition of ferroptosis to alleviate ischemic acute kidney injury ^[23][57]. Pretreatment with hepcidin prevents renal IRI-induced dysregulation of systemic iron homeostasis and reduces inflammation in AKI animal models ^[24][58]. These findings suggest that the hepcidin–ferroportin pathway holds promise as a novel therapeutic target in the treatment of AKI.

Lipid peroxidation is responsible for intense vasoconstriction and oxidative injury, which is an unfavorable factor for AKI ^[25][26][59,60]. Inhibition of lipid peroxidation can alleviate kidney injury induced by cistplatin ^[27][61]. It has been reported that treatment with lipophilic antioxidants, diphenyl-p-phenylenediamine (DPPD), and deferoxamine suppresses the accumulation of thiobarbituric acid reactive substances in proximal tubules injured by tert-butyl hydroperoxide (tBHP) ^[28][62]. Quercetin, a natural flavonoid, has been shown to block the typical morphologic changes of ferroptotic cells by reducing the levels of malondialdehyde (MDA) and lipid ROS as well as increasing the levels of GSH in proximal tubular epithelial cells ^[29][63]. Treatment with quercetin abrogated lipid ROS and protected functional acute renal failure and structural organ damage in AKI mice ^[29][63]. In sum, all the studies directly or indirectly support an essential role of ferroptosis in AKI.

CKD, also known as chronic kidney failure, is defined as the presence of kidney damage persisting over a long period of time. CKD can cause wastes to build up in the body and is a worldwide public health problem with adverse outcomes, including loss of kidney function, cardiovascular disease (CVD), and premature death. The causes of CKD might vary globally.

Iron homeostasis is maintained by multiple mechanisms, such as hepcidin and iron regulatory proteins (IRPs), at the systemic and cellular levels. In normal human kidneys, IRPs in proximal tubules regulate tubular iron handling to avoid iron accumulation. However, in CKD patient kidneys, iron is deposited and results in increased iron uptake and/or inadequate iron export ^[30][66]. The accumulation of irons initiates Fenton-mediated oxidative damage and may contribute to renal injury ^[31][32][67,68], suggesting that the CKD kidney iron accumulation is initially inducing ferroptosis and iron plays a detrimental role in the progression of CKD. Therefore, the regulation of iron metabolism proteins is of great significance in restoring kidney iron metabolism and mitigating ferroptosis.

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease and accounts for most mortality in patients with diabetes mellitus ^[33][69]. Diabetic nephropathy (DN), a severe microvascular complication of diabetes, is characterized by proteinuria and a progressive decline in kidney function, leading to the end-stage of kidney disease ^[34][70]. The diabetic kidney is exposed to high glucose, oxidative stress, and advanced glycation end products, which contribute to the progression of nephropathy by inducing glomerular cell activation and inflammatory infiltration ^[35][71]. Accumulative studies have indicated that in addition to many forms of programmed cell death, such as autophagy, apoptosis, and necrosis, ferroptosis also plays a pathological role in the development of DN ^[36][72]. In diabetic nephropathy of kidney biopsy tissues, the ferroptosis-related molecules SlC7A11 and GPX4 are decreased compared to non-DN patients ^[37][73]. The involvement of ferroptosis has also been confirmed in streptozotocin-induced DN animal models ^[36][72]. There were significant changes in ferroptosis-associated markers, including decreased expression levels GPX4 and increased expression of ACSL4 as well as lipid peroxidation products, and iron content in DN mice. Treatment with ferroptosis inducer, erastin or RSL3, could induce renal tubular cell death and increase the levels of iron and ACSL4 to sensitize those cells to ferroptosis ^[36][72]. Treatment with ACSL4 inhibitor, rosiglitazone, reduced lipid peroxidation product MDA and iron content in kidneys of DN mice, resulting in the improvement in survival rate and kidney function in those mice ^[36][72]. The role of ferroptosis in the development of DN is also supported by the finding that treatment with high glucose led to ferroptosis-specific mitochondrial changes in the HK-2 cells, whereas treatment with Fer-1 significantly rescued these changes and alleviated the renal pathological injuries in diabetic DN mice through Nrf2 pathway ^[38][74]. Treatment with Fer-1 also significantly ameliorated kidney hypertrophy and albuminuria to reduce the intracranial accumulation of lipid peroxidation in the diabetic mice by the HIF-1α/HO-1 pathway ^[39][75]. In addition, it has also been reported that HO-1 is expressed specifically in glomeruli in DN, and the induction of HO-1 prevents podocyte apoptosis ^[40][41][76,77]. Treatment with the antioxidant tempol increased the HO-1 activity in DN mice, resulting in the inhibition of oxidative stress and the restoration of redox balance ^[42][78]. Thus, induction of HO-1 may be beneficial for DN.

HMGB1 is a DNA-binding nonhistone protein and implicated in DNA replication, transcription, and DNA damage repair ^[43][79]. In addition to its nuclear functions, extracellular HMGB1 is a damage-associated molecular that triggers the inflammation and immunity response during ferroptosis induced by RSL3 and elastin in vitro ^[44][80]. In DN patients, HMGB1 are significantly elevated. Knockdown of HMGB1 suppressed high glucose-induced activation of TLR4/NF-κB axis and promoted Nrf2 expression as well as its downstream targets, including HO⁻¹, NAD(P)H dehydrogenase (quinone 1) (NQO-1), glutamate–cysteine ligase catalytic subunit (GCLC), and glutamate–cysteine ligase modifier subunit (GCLM) in mesangial cells in vitro ^[45][81], which suggested that targeting HMGB1 for ferroptosis might be a novel therapeutic strategy in diabetic kidney disease.

Renal fibrosis is considered the common pathway of chronic progressive kidney disease ^[46][82]. Emerging evidence shows that ferroptosis is an integral process in the pathogenesis of renal fibrosis. TGF-β1 has been considered as a key mediator of renal fibrosis ^[47][83]. Treatment with TGF-β1 decreased the SLC7A11 and GPX4 expression in renal tubular cells and co-treatment with Fer-1 abrogates TGF-β1-induced cell death in vitro ^[37][73]. In doxorubicin induced-renal fibrosis animals, the non-heme iron levels, and the mRNA of renal prostaglandin–endoperoxide synthase 2 (PTGS2), a putative marker of ferroptosis, were increased in kidneys, which suggested a possible role of ferroptosis in renal fibrosis ^[48][84]. In unilateral ureter obstruction (UUO) or IRI indued fibrosis mouse kidneys, the expression of GPX4 was downregulated and the expression of 4-hydroxynonenal (4-HNE), the lipid peroxidation production, was upregulated ^[49][50][85,86]. In addition, the expression of HO-1 was peaked in mouse kidneys at 12 h after obstruction but decreased in kidneys one week after UUO ^[51][87]. Knockout of HO-1 (^−/−) increased renal EMT and fibrosis as well as macrophage infiltration and the expression of renal tubular TGF-β 1 after 7 days of UUO compared to those in wild-type UUO mice ^[52][88]. Moreover, the induction of HO-1 inhibited the expression of TGF-β1 and proinflammatory molecules, and also reversed renal tubule-interstitial fibrosis ^[53][89]. Targeting ferroptosis with inhibitors, including Fer-1 and deferoxamine (DFO), could largely mitigate kidney injury, interstitial fibrosis, and inflammatory cell accumulation in mice after UUO or IRI injury ^[49][50][85,86]. In addition, treatment with tocilizumab mimotopes alleviates kidney injury and fibrosis by ferroptosis inhibition in a UUO model ^[54][90]. Iron chelation is considered as a possible treatment for renal fibrotic lesions ^[55][91]. In a CKD rat model, treatment with deferasirox (DFX), could mitigate renal fibrosis by inhibiting TGF-β1/Smad3, inflammation, and oxidative stress pathways ^[56][92]. Moreover, an iron-restricted diet exerts a renal protective effect by inhibiting oxidative stress and aldosterone receptor signaling in animal models of CKD ^[57][58][93,94].

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, which is caused by mutations of PKD1 (encoding polycystin-1) or PKD2 (encoding polycystin-2) and is characterized by multiple cysts in the kidneys which enlarge over time and lead to end-stage renal disease failure ^[59][95]. Cyst formation and progression in ADPKD are also involved in oxidative stress and inflammation and cell death ^[60][61][62][96,97,98]. It has been reported that the expression of antioxidant enzymes (such as GPX and SOD) and their activity were decreased in two different PKD animal models ^[63][99]. In addition, lipid peroxidation is increased in human polycystic kidneys and cyst growth is augmented by the lipid-peroxidizing compound tBHP in mouse embryonic kidney organ cultures ^[64][100]. IRecent wasly, we showed that inhibition of ferroptosis with Fer-1 delays cyst growth in rapidly and slowly progressive ADPKD mouse models, whereas induction of ferroptosis with its inducer, erastin, promotes cyst growth in those mouse models ^[65][15]. EvidencWe was provided evidence to support that low levels of cell death in kidneys from Pkd1 mutant mouse models are mainly ferroptotic, not apoptotic. The expression of the system Xc-, which are critical for the import of cystine (SLC7A11 and SLC3A2), the iron exporter (ferroportin), and GPX4 was decreased, and the expression of iron importers (TFR1, DMT1) and HO-1 was increased in Pkd1 mutant renal epithelial cells and tissues, resulting in high iron levels, low GSH and GPX4 activity, increased lipid peroxidation, and proneness to ferroptotic cell death. In addition, it waswe showed that 4HNE, a lipid peroxidation product, is increased in Pkd1 null cells which is responsible to promote the proliferation of Pkd1 mutant cells via activation of Akt, S6, Stat3, and Rb. Collectively, it was our recent study suggests that ferroptosis is one of the important mechanisms to promote cyst progression in ADPKD and targeting ferroptosis may be a novel therapeutic strategy got ADPKD treatment ^[65][15].

Kidney cancer, also known as renal cancer, is defined as a disease that starts in the kidneys. It is one of the top 10 most common cancers in the United States with more than 76,000 new cases diagnosed each year. A retrospective cohort study found that 26% of kidney cancer patients had CKD before tumor nephrectomy ^[66][101]. The cause of developing kidney cancer is still not clear. However, there are several factors that can increase the risk of kidney cancer, such as older age, smoking, obesity, hypertension, and being on kidney dialysis. RCC, also known as renal cell adenocarcinoma, is the most common type of kidney cancer in adults. A study demonstrated the risk of RCC in ESRD patients is increased up to 100 times ^[67][102]. RCC denotes cancer originated from the renal epithelium and accounts for >90% of cancers in the kidney and can be distinguished by histopathological features and gene mutations ^[68][103]. Localized RCC can be successfully manage with surgery, whereas metastatic RCC is refractory to conventional chemotherapy in which most patients show resistance to chemotherapy and radiotherapy. Activation of regulated cell death is considered an ideal therapeutic strategy for cancer and may help drug resistance. Research on the effect of erastin in 60 tumor cell lines of eight tissues found that RCC cells are more susceptible than others to erastin induced cell death ^[69][104]. Clear cell renal cell carcinoma (ccRCC) is the most common type of RCC. Both hereditary and familial ccRCC are strongly connected with von Hippel Lindau (VHL) gene mutations, which consecutively lead to the stabilization of hypoxia-inducible transcription factor (HIF) ^[70][105]. Miess et al. demonstrated that the silence of genes coding for glutathione peroxidases, GPX3 and GPX4, is lethal to ccRCC cells ^[71][106]. They also found that the cell viability of ccRCC is dependent on the synthesis of GSH, which prevents the accumulation of lipid peroxides. In addition, the re-expressed VHL gene had a resistance effect on ferroptosis in VHL-deficient RCC cells ^[71][106]. In addition, the susceptibility of ferroptosis can be affected by cell density and this effect is mediated by TAZ through the regulation of EMP1-NOX4 in ccRCC ^[72][107]. Furthermore, a 2–82% mutation rate among 36 ferroptosis associated genes (FRGs), including TP53, NFE2L2, FANCD2, DPP4, ALOX5, PTGS2, ALOX15B, ACSL4, CARS, and HMGCR, was detected in ccRCC in an analysis based on the GSCA database ^[73][108]. A new survival model was built based on five risk-related FRGs (CARS, NCOA4, FANCD2, HMGCR, and SLC7A11), which indicated that high expression of FANCD2, CARS, and SLC7A11 and low expression of HMGCR and NCOA4 are associated with high-risk ccRCC patients. These studies suggest that FRGs are the potential prognostic biomarkers and ferroptosis modulation may have therapeutic potentials in ccRCC.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) are the autosomal dominant disorder caused by germline mutations in fumarate hydratase (FH), which is characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas, and papillary type 2 renal cancer, which is resistant to current radiotherapy, chemotherapy, and immunotherapy ^[74][109]. It has been suggested that accumulated fumarate drives constitutive Nrf2 activation, which promotes the transcription of FTL and FTH1 genes in HLRCC cells in vitro ^[75][110]. On one side, excessive fumarate inhibits IRPs’ ability via the repression of FTL and FTH1 mRNA translation, which results in high intracellular ferritin levels ^[76][111]. High intracellular ferritin further sequesters free iron and finally results in a drop in the labile iron pool. On the other side, the FH accumulation sensitizes HLRCC cells to ferroptosis through C93 modification which represses GPX4 activity ^[77][112]. FH is also shown to indirectly inhibit AMPK, resulting in indirect inhibition of DMT1 expression ^[76][111]. This prevents the efflux of iron from the endosome into the cytoplasm to further reduce the labile iron pool. Induction of ferroptosis in FH-inactivated tumors represents an opportunity for synthetic lethality in cancer. Thus, pharmacological suppression of those proteins represents a treatment strategy worth exploring.