CORM-401

CORM-401 is a manganese-containing carbon monoxide-releasing molecule. CORM-401 can release CO in the presence of oxidants to exert anti-inflammatory and antioxidant stress effects. CORM-401 regulates cellular metabolism by uncoupling mitochondrial respiration and inhibiting glycolysis. CORM-401 can be used in research on ischemia-reperfusion injury, inflammatory diseases, metabolic diseases, and periodontitis^[1-4].

In vitro, BV2 cells were treated with 5-500µM CORM-401 for 0-400 minutes. Low concentrations (5µM, 10µM) increased oxygen consumption rate and maintained ATP levels. Concentrations of 50µM and above first briefly stimulated and then inhibited respiration and reduced ATP. CORM-401 uncoupled the mitochondrial respiratory chain^[5]. A549 cells were treated with mitochondria-targeted nanoparticles CORM-TPP@HA containing CORM-401 (5-40µg/mL) for 24 hours. The treatment inhibited A549 cell viability, elevated mitochondrial ROS, intracellular copper, and cuproptosis-related proteins ATOX1, ATP7A, and COX17^[6]. EA.hy926 cells were treated with 30-100µM CORM-401 for 1 hour. The treatment induced NO production, increased NADPH concentration, accelerated the pentose phosphate pathway, and reduced the ratio of reduced to oxidized glutathione (GSH/GSSG)^[7].

In vivo, C57BL/6 mice with high-fat diet-induced obesity were intragastrically administered 30mg/kg CORM-401 three times per week for 14 weeks. CORM-401 reduced body weight gain, lowered fasting blood glucose and insulin levels, and improved HOMA-IR^[8]. Healthy control mice and sickle cell disease (SS) mice were orally given 30mg/kg CORM-401 three times per week for 3 weeks. CORM-401 increased blood carboxyhemoglobin levels and hepatic carbon monoxide accumulation, reduced inflammatory cell infiltration, thrombosis, and iron deposition in the lungs, liver, and kidneys of SS mice, decreased pulmonary macrophage iron accumulation, reduced plasma white blood cell counts in SS mice, and alleviated the rise in blood urea nitrogen^[9]. Male C57BL/6J mice fed a high-fat diet were intragastrically administered 30mg/kg CORM-401 three times per week for 7 weeks. CORM-401 reduced body weight and white adipose tissue mass, decreased adipocyte size, lowered triglyceride content in white adipose tissue, and reduced hepatic fat accumulation^[10].

References:

[1] Bauer N, Yuan Z, Yang X, et al. Plight of CORMs: The unreliability of four commercially available CO-releasing molecules, CORM-2, CORM-3, CORM-A1, and CORM-401, in studying CO biology. Biochem Pharmacol. 2023 Aug;214:115642.

[2] Chen Y, Chen H, Li Z. Multifunctional peptide-drug conjugate CORM-401@R9: A novel approach to combat oxidative stress in cataracts. Free Radic Biol Med. 2025 Feb 1;227:570-581.

[3] Bauer N, Mao Q, Vashistha A, et al. Compelling Evidence: A Critical Update on the Therapeutic Potential of Carbon Monoxide. Med Res Rev. 2025 Jul;45(4):1275-1301.

[4] Yao S, Wang Y, Shao L, et al. Injured renal cell membrane encapsulated ICG/CORM-401 for homologous targeted NIR theranostics of acute kidney injury. Journal of Nanobiotechnology. 2025 Aug 26;23:589.

[5] Wilson JL, Bouillaud F, Almeida AS, et al. Carbon monoxide reverses the metabolic adaptation of microglia cells to an inflammatory stimulus. Free Radic Biol Med. 2017;104:226-242.

[6] Shao L, Song Z, Gong X, et al. Mitochondria-targeted CORM-401 nanoparticles inhibit A549 cells by triggering cuproptosis. BMC Biotechnol. 2026;26(64).

[7] Kaczara P, Proniewski B, Lovejoy C, et al. CORM-401 induces calcium signalling, NO increase and activation of pentose phosphate pathway in endothelial cells. FEBS J. 2018;285(7):1346-58.

[8] Braud L, Pini M, Muchova L, et al. Carbon monoxide-induced metabolic switch in adipocytes improves insulin resistance in obese mice. JCI Insight. 2018 Nov 15;3(22):e123485.

[9] Nguyen KA, Matte A, Foresti R, et al. An oral carbon monoxide-releasing molecule protects against acute hyperhemolysis in sickle cell disease. Blood. 2024 Jun 13;143(24):2544-58.

[10] Klemola E, Posio K, Karpale M, et al. Carbon monoxide-releasing molecule CORM-401 treatment elicits corticosterone-driven stress lipolysis and tissue-specific hypoxia-inducible factor activation. Redox Biology. 2026;95:104295.