Table 1.

Key factors in p53-mediated ferroptosis.

Category of regulator	Name of regulator	Promote (+) or inhibit (–) p53-ferroptosis pathway	Mechanism of action	Physiopathological relevance	Reference
Post-translational protein modification	CREB binding protein (CBP)	+	Acetylate p53 at K101 to boost its suppressive effect on SLC7A11	Promote the tumor-suppressive function of p53	[23, 79]
	Sirtuins	–	Deacetylate p53 to block its suppressive effect on SLC7A11	(1) Protect cardiomyocyte (SIRT1) and neural cell (SIRT2) from ischemia/reperfusion-induced cell death (2) Inhibit the tumor-suppressive function of p53 (SIRT3)	[81–83]
	Suppressor of cytokine signaling 1 (SOCS1)	+	Activate ataxia telangiectasia mutated (ATM) to phosphorylate p53 at S15 and stabilize p53 by interfering tripartite motif containing 28 (TRIM28 or KAP1)	Promote the tumor-suppressive function of p53	[84]
	Mitogen-activated protein kinase kinase kinase 11 (MLK3)	+	Activate mitogen-activated protein kinase 8 (JNK) to phosphorylate and stabilize p53	Contribute to pressure overload-induced myocardial fibrosis	[85]
	Toll-like receptor 4 (TLR4)	+	Activate p38 to phosphorylate p53 to enhance its activity	Contribute to hypoxic-ischemic brain damage (HIBD)	[88]
	Bromodomain containing 7 (BRD7)	+	Promote p53 S392 phosphorylation and mitochondrial localization	Promote ferroptosis in hepatic stellate cells (HSCs) to ameliorate the damage of liver fibrosis	[35]
	Deubiquitinase ubiquitin-specific peptidase 7 (USP7, or HAUSP)	+	Deubiquitinate and stabilize p53 to upregulate transferrin receptor 1 (TfR1)	Contribute to ischemia/reperfusion-induced myocardial injury	[90]
Single-nucleotide polymorphism (SNP)	p53 P47S variant	–	Decrease the ability of p53 to inhibit SLC7A11, increase the cellular levels of CoA and GSH, and produce a ferroptosis-resistant metabolic state in cells	Decrease the ability of p53 to suppress tumor and Plasmodium infection, but enhance the response to the malarial toxin hemozoin	[26–30]
Non-coding RNA	P53RRA	+	Bind G3BP stress granule assembly factor 1 (G3BP1) to abolish its repressive effect on p53	Promote the tumor-suppressive function of p53 in breast and lung cancers	[91]
	Meg3	+	Upregulate p53 level to suppress GPX4	Contribute to oxygen and glucose deprivation combined with hyperglycemia-induced diabetic brain ischemic injury	[92]
	PVT1	+	Sponge miR-214 to abolish its repressive effect on p53	Contribute to ischemia/reperfusion-induced brain injury	[93]
	CircKDM4C	+	Sponge hsa-let-7b-5p to abolish its repressive effect on p53	Promote the tumor-suppressive function of p53 in acute myeloid leukemia	[58]
Small molecule, ROS, iron, nutrient, cytokine, waste, and light	CoA	–	Inhibit the oligomerization and activity of p53	Enhance the cellular resistance to ferroptosis	[27]
	GSH
	ROS	+	Activate the p53/SLC7A11 pathway	Promote the tumor-suppressive function of p53 in lung cancer	[97]
	Iron overload	+	Activate the p53/SLC7A11 pathway	Contribute to sarcopenia, Parkinson’s disease, and ischemia-induced hippocampal neuronal death	[98–100]
	High glucose	+	Activate the p53/SLC7A11 pathway	Contribute to diabetes-induced endothelial dysfunction	[101]
	Interleukin-1β (IL-1β)
	High calcium oxalate (CaOx)	+	Increase the levels of p53, ACSL4, transferrin, and TfR	Contribute to the renal crystal deposition and the development of urolithiasis	[102]
	High fluence of blue light (HFBL)	+	Activate p53	May be associated with light pollution and may be used to treat p53-ferroptosis pathway-related diseases	[103]
Others	N-acylsphingosine amidohydrolase (ASAH2)	–	Destabilize p53	Decrease the ability of p53 to suppress tumor by promoting the accumulation of myeloid-derived suppressor cells (MDSCs) in colon cancer microenvironment	[95]
	Lymphoid-specific helicase (LSH)	–	Inactivate p53	Decrease the ability of p53 to suppress tumor	[38]
	Cytoglobin (CYGB)	+	Activate p53/YAP1/ACSL4 pathway	Promote the tumor-suppressive function of p53 in colon cancer	[59]