Table 1.

Therapeutic agents targeting ferroptosis and inflammation.

Therapeutic strategy	Representative agents	Primary target/pathway	Mechanism	Protective effects on testis	Evidence status/translational stage	References
Iron chelators	Deferoxamine (DFO), Deferiprone (DFP)	Labile iron pool/Fenton reaction	Chelate Fe²+, inhibit ROS amplification and lipid peroxidation	Reduce Sertoli cell ferroptosis, protect spermatogenesis and blood-testis barrier integrity	Clinically approved for iron overload disorders; application in radiation-induced testicular injury remains preclinical	(73)
Lipophilic radical scavengers	Ferrostatin-1 (Fer-1), Liproxstatin-1 (Lip-1)	Lipid ROS/membrane phospholipids	Scavenge lipid radicals, terminate lipid peroxidation chain reaction	Reduce germ cell loss, mitochondrial damage, and membrane oxidative injury	Experimental ferroptosis inhibitors; no clinical application currently	(74, 75)
GPX4 restoration	Selenium, L-selenomethionine	GPX4-dependent antioxidant defense	Enhance GPX4 synthesis and detoxification of phospholipid hydroperoxides	Improve sperm quality and antioxidant capacity	Nutritional compounds with clinical availability; ferroptosis-targeting application requires further validation	(76, 77)
System Xc- activation	N-acetylcysteine (NAC), Sulforaphane	SLC7A11/GSH biosynthesis	Restore cysteine uptake and intracellular GSH pool, support GPX4 activity	Enhance endogenous antioxidant capacity, inhibit ferroptosis	NAC clinically available; protective effects against radiation-induced testicular injury remain insufficiently validated	(78)
NRF2 activators	Sulforaphane, Bardoxolone methyl	NRF2/Keap1 signaling pathway	Upregulate antioxidant and iron-related genes (SLC7A11, FTH1, HO-1, GCLC)	Protect redox homeostasis in Leydig and Sertoli cells	Mostly preclinical; clinical translation for reproductive protection remains unclear	(79, 80)
Ferritinophagy inhibition	3-Methyladenine (3-MA), autophagy inhibitors	NCOA4-mediated ferritinophagy	Prevent ferritin degradation and excessive free iron release	Reduce iron overload and secondary ferroptosis	Experimental strategy; clinical applicability remains limited	(81)
Mitochondrial protection	Coenzyme Q10 (CoQ10), MitoQ	Mitochondrial ROS/membrane potential	Stabilize mitochondrial membrane integrity, inhibit mitochondrial lipid peroxidation	Improve ATP production, sperm motility, and Leydig cell steroidogenesis	CoQ10 is clinically available as a supplement; ferroptosis-related reproductive protection remains investigational	(82–84)
Melatonin-mediated ferroptosis inhibition	Melatonin	NRF2/GPX4 axis, mitochondrial ROS, inflammatory signals	Enhance antioxidant defense, inhibit lipid peroxidation and ferroptosis, modulate immune responses	Protect spermatogenic cells, alleviate testicular injury induced by heat stress, chemotherapy, and ischemia	Clinically available compound; radioprotective effects in testicular injury remain preclinical	(85)
Anti-inflammatory intervention	NSAIDs, TNF-α inhibitors, Pentoxifylline	TNF-α/NF-κB signaling pathway	Inhibit inflammatory amplification triggered by ferroptosis-associated DAMPs	Reduce blood-testis barrier disruption and inflammatory damage	Clinically available drugs; application in ferroptosis-associated testicular injury remains preclinical	(86, 87)
HMGB1 blockade	Anti-HMGB1 antibody, RAGE/TLR4 antagonists	HMGB1-TLR4/RAGE axis	Inhibit DAMP-mediated macrophage activation and cytokine release	Prevent progression of chronic sterile inflammation and autoimmune orchitis	Experimental strategy; clinical application for testicular injury remains unavailable	(88)
Macrophage reprogramming	IL-10, MSC-derived exosomes	M1/M2 polarization	Promote anti-inflammatory M2 phenotype, suppress cytokine storm	Restore immune privilege, stabilize testicular microenvironment	Emerging immunomodulatory strategy; currently limited to preclinical studies	(89)
Natural antioxidants	Curcumin, Quercetin, Lycopene, Vitamins C/E	ROS and lipid peroxidation	Neutralize ROS, improve endogenous antioxidant enzyme activities	Protect sperm DNA integrity, improve semen parameters	Widely available compounds; protective effects against ferroptosis-related injury remain mainly preclinical	(90–94)
Clinically available ferroptosis-related antioxidant combinations	NAC + selenium, CoQ10 + L-carnitine	GSH-GPX4 system, mitochondrial antioxidant network	Synergistically inhibit lipid peroxidation and oxidative-inflammatory damage	Improve semen quality, protect germ cells from oxidative injury	Clinically accessible combinations; application in radiation-induced ferroptosis remains investigational	(95–98)
Drug repurposing (ferroptosis inhibitor)	Edaravone	Lipid ROS, NRF2/GPX4 signaling pathway	Potent free radical scavenger, inhibits lipid peroxidation and ferroptosis	Potential protective effect against testicular ischemia-reperfusion and toxin-induced injury	Repurposed compounds with preclinical evidence; translational potential requires further validation	(99)
Stem cell/exosome therapy	MSC-derived exosomes	Tissue repair and immunomodulation	Deliver anti-inflammatory miRNAs and antioxidant proteins	Promote blood-testis barrier repair and regeneration of spermatogenic microenvironment	Promising regenerative approach; currently restricted to preclinical studies	(100)
Nanomedicine delivery	Lipid nanoparticles, ROS-responsive nanocarriers	Targeted ferroptosis modulation	Improve bioavailability and testicular targeting of ferroptosis inhibitors	Enhance therapeutic precision, reduce systemic toxicity	Early translational strategy; mainly supported by preclinical evidence	(101, 102)
Combination therapy	Fer-1 + anti-inflammatory drugs; NAC + selenium; CoQ10 + antioxidants	Ferroptosis-immune amplification loop	Simultaneously block lipid peroxidation and inflammatory signals	More effectively restore blood-testis barrier integrity and fertility potential	Emerging strategy; efficacy and clinical translation remain to be established	(103, 104)