Notably, landmark clinical progress has been achieved: The catalytic nanocrystal suspension CNM-Au8, a therapeutic candidate for amyotrophic lateral sclerosis, has advanced to phase II clinical trials. This review systematically summarizes the core catalytic mechanisms of antioxidant nanozymes, clarifies the structure-activity relationships between rational material design and catalytic performance, reviews the latest advances in their biomedical applications, and dissects the key bottlenecks restricting preclinical research and clinical translation. It aims to provide rational design principles for researchers in this field, reduce empirical trial and error in material development, and provide guidance for the further optimization and clinical translation of antioxidant nanozymes.

P1/2, N=49, Completed, Nacuity Pharmaceuticals, Inc. | Active, not recruiting --> Completed

P3, N=80, Not yet recruiting, Nacuity Pharmaceuticals, Inc. | Trial completion date: Dec 2028 --> Jul 2029 | Initiation date: Jun 2026 --> Dec 2026 | Trial primary completion date: Dec 2028 --> Jul 2029

P=N/A, N=74, Completed, Shionogi | Active, not recruiting --> Completed | N=300 --> 74

P1/2, N=12, Active, not recruiting, Nacuity Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting

The L/Z complex confers retinal protection through coordinated antioxidant and anti-inflammatory mechanisms in both cellular and animal models of retinal injury, supporting its translational potential as a nutritional intervention for retinal degeneration.

SFN confers neuroprotection in SCI by reducing oxidative stress, modulating JAK/STAT signaling, rebalancing microglial polarization, and improving locomotor recovery. These findings highlight SFN as a promising candidate for therapeutic development in SCI.

Further, zileuton suppressed colony formation in both breast cancer cell lines. Data suggest that 5-LOX may serve as a potential therapeutic target for breast cancer, and zileuton warrants further investigation as a candidate anti-cancer agent.

Pharmacological rescue experiments using dorsomorphin and TBHQ confirmed the involvement of the AMPK/mTOR/NCOA4 and Nrf2/SLC7A11/GPX4 pathways, respectively. Furthermore, GRk1 synergistically potentiated the cytotoxic effects of cisplatin. In a xenograft mouse model, GRk1 effectively inhibited tumor growth without inducing significant systemic toxicity. Collectively, these findings identify GRk1 as a potent natural ferroptosis inducer and support its potential development as a promising adjuvant therapeutic strategy for OS.

Nebivolol exerts nephroprotective effects via antioxidant and anti-inflammatory pathways, preventing cyclophosphamide-induced renal dysfunction. These beneficial effects suggest nebivolol could help prevent the renal toxicity associated with cyclophosphamide.

P1, N=10, Recruiting, University of Texas Southwestern Medical Center | Not yet recruiting --> Recruiting

In preclinical models, pharmacological agents including montelukast, zileuton, and FLAP antagonists suppress tumor growth, and restore apoptotic signaling; current clinical evidence remains largely observational and pharmacoepidemiologic. Targeting this pathway represents a promising avenue in oncology, with potential to enhance precision medicine through biomarker-guided patient stratification. Further clinical validation is warranted to translate these findings into therapeutic benefit.