The Efficacy of Ferroptosis Inhibition on Ischemia–reperfusion Injury of Abdominal Organs: A Systematic Review and Meta-analysis

Solid organ transplantation is hampered by complications that arise after ischemia–reperfusion injury (IRI), a detrimental type of injury for which no adequate treatment options are available. Ferroptosis, an iron-dependent form of regulated cell death, is a major driver of IRI. This systematic review and meta-analysis summarizes the effects of pharmacological ferroptosis inhibition in abdominal organs in the setting of IRI. PubMed, Embase, Web of Science and Cochrane were searched for concepts “ferroptosis” and “IRI” in August 2023. To allow for meta-analyses, inhibitors were divided into different intervention pathways: (I) lipophilic radical scavengers, (II) iron chelators, (III) antioxidants, (IV) lipid metabolism inhibitors, (V) combination treatments, and (VI) others. When available, organ function and injury effect sizes were extracted and used for random-effects meta-analyses. In total 79 articles were included, describing 59 unique inhibitors in kidney, liver, and intestinal IRI. No studies in pancreas were found. Overall bias and study quality was unclear and average to low, respectively. Apart from 1 clinical study, all inhibitors were tested in preclinical settings. The vast majority of the studies showed ferroptosis inhibition to be protective against IRI under various treatment conditions. In liver and kidney IRI, meta-analyses on standardized effect sizes from 43 articles showed a combined protective effect against IRI compared with a nontreated controls for all analyzed intervention pathways. In conclusion, ferroptosis inhibition protects against abdominal IRI in preclinical research. Important questions regarding optimal intervention pathway, bioavailability, optimal dosage, side effects etc. should be addressed before clinical introduction.