Sažetak
Background: Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation and has been increasingly implicated in the pathogenesis of severe infections and critical illness. Acyl-CoA synthetase long-chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4) are key regulators of ferroptosis and may serve as clinically useful biomarkers for prognostic assessment. This systematic review and meta-analysis aimed to evaluate the prognostic significance of serum ACSL4 and GPX4 levels in critically ill patients with severe infections.
Methods: A systematic search of PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data, and China Biology Medicine Disc (CBM) was conducted from database inception to March 2026. Observational studies evaluating the association between serum ACSL4 and/or GPX4 levels and clinical outcomes in critically ill patients were included. Study quality was assessed using the Newcastle–Ottawa Scale (NOS). Meta-analysis was performed using RevMan 5.4 and Stata 16.0. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using random-effects models. Diagnostic performance was evaluated using receiver operating characteristic (ROC) data where available. Heterogeneity, sensitivity analyses, and publication bias assessments were conducted according to standard methodological approaches.
Results: A total of 42 records were identified, and two high-quality prospective cohort studies involving 437 critically ill patients were included. NOS scores ranged from 8 to 9 points. Meta-analysis demonstrated that ferroptosis-related biomarkers were significantly associated with short-term mortality. Reduced serum GPX4 (OR=1.076, 95% CI: 1.036–1.119), reduced GSH/GSSG ratio (OR=1.258, 95% CI: 1.161–1.364), and elevated serum ACSL4 (OR=4.00, 95% CI: 2.00–8.00) were independently associated with adverse outcomes. The pooled OR was 1.76 (95% CI: 1.03–3.01), indicating a significantly increased risk of short-term mortality in patients exhibiting ferroptosis pathway dysregulation. Regarding prognostic performance, ACSL4 alone yielded an area under the curve (AUC) of 0.713, whereas GPX4 alone showed limited predictive ability (AUC=0.573). Combined assessment of GPX4 and GSH/GSSG improved predictive performance substantially (AUC=0.841). Sensitivity analyses confirmed the robustness of the findings.
Conclusion: Abnormal expression of ferroptosis-related biomarkers, particularly elevated ACSL4 and reduced GPX4 levels, is associated with poor short-term outcomes in critically ill patients with severe infections. Combined evaluation of ferroptosis-related markers may improve risk stratification and prognostic assessment. These findings support the potential clinical utility of the ACSL4/GPX4 axis as a biomarker system and highlight ferroptosis as a promising therapeutic target in critical illness.
Ključne reči
GPX4
Ferroptosis
Critical illness
Sepsis
Community-acquired pneumonia
Prognosis
The published articles will be distributed under the Creative Commons Attribution 4.0 International License (CC BY). It is allowed to copy and redistribute the material in any medium or format, and remix, transform, and build upon it for any purpose, even commercially, as long as appropriate credit is given to the original author(s), a link to the license is provided and it is indicated if changes were made. Users are required to provide full bibliographic description of the original publication (authors, article title, journal title, volume, issue, pages), as well as its DOI code. In electronic publishing, users are also required to link the content with both the original article published in Journal of Medical Biochemistry and the licence used.
Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.