Forward genetic approaches using Caenorhabditis elegans for uncovering novel regulators of ferroptosis

Abstract

Ferroptosis, an iron-dependent form of regulated cell death characterised by lipid peroxidation, has emerged as a critical pathway in cancer, neurodegeneration, and ischaemia-reperfusion injury. While reverse genetic approaches have dominated ferroptosis research, forward genetic strategies offer unique advantages for discovering novel regulatory mechanisms without prior knowledge of pathway components. This perspective explores how classical forward genetic methodologies, including chemical mutagenesis screens, genetic modifier studies, and quantitative trait locus mapping, can be adapted to systematically identify ferroptosis regulators. We focus on employing the nematode model,Caenorhabditis elegans, and discuss the inherent advantages and disadvantages of this system. Technical considerations for designing phenotype-based screens are discussed, highlighting successful examples from related cell death pathways. Experimental frameworks for leveraging alternate model organisms to uncover conserved ferroptosis mechanisms are also explored. Forward genetics promises to reveal unexpected connections between ferroptosis and cellular processes, potentially identifying new therapeutic targets and biomarkers for ferroptosis-related diseases.

Keywords

Ferroptosis / forward genetics / Caenorhabditis elegans / mutagenesis / phenotype screening / cell death

Authors contribution

Ng CY: Conceptualisation, writing-original draft, writing-review & editing. Jenkins NL, Bush AI: Writing-review & editing. McColl G: Supervision, visualisation, writing-review & editing.

Conflicts of interest

Ashley I. Bush is an Editor of Ferroptosis and Oxidative Stress. He is also a shareholder in Alterity Therapeutics Ltd and Cogstate Ltd, and has a profit-share arrangement with Collaborative Medicinal Development Pty Ltd. The other authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by an ARC Discovery project (Grant No. DP230102244), the Victorian Government’s Operational Infrastructure Support Program (This program does not have a grant number), Medical Research Future Fund Dementia, Ageing and Aged Care (Grant No. MRFF2007656 to Ashley I. Bush), a National Health & Medical Research Council Leadership 3 fellowship (Grant No. GNT2041278 to Ashley I. Bush), and the University of Melbourne through a Melbourne Research Scholarship to Chong Yi Ng (This program does not have a grant number).

Copyright

© The Author(s) 2026.

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