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While artemisinin resistance has not yet been observed in the region, molecular surveillance in sub-Saharan Africa has identified Plasmodium falciparum k13 mutations known to confer resistance, making it vitally important to take proactive and creative measures to protect current treatment regimens. Glutathione S-transferases (GSTs), the multifunctional enzymes involved in detoxification and redox control, have emerged as key contributors to drug resistance in Plasmodium species. The role of GSTs in the development of resistance is discussed in the review, and GSTs are presented as prospective molecular targets for the development of novel therapeutic interventions. We examine the complexity of antimalarial resistance in Southern Africa and highlight the potential of GST inhibition as an adjunct therapy to current malaria control measures. The review promotes a paradigm shift towards GST-targeting approaches as a pre-emptive strategy to avert resistance and consolidate malaria control initiatives throughout the region, aligning with Sustainable Development Goal 3 (good health and wellbeing) among Southern African populations.<\/jats:p>","DOI":"10.1093\/lambio\/ovaf100","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T11:20:03Z","timestamp":1753096803000},"source":"Crossref","is-referenced-by-count":2,"title":["Targeting\n                    <i>Plasmodium<\/i>\n                    glutathione S-transferases to overcome antimalaria drug resistance in Southern Africa"],"prefix":"10.1093","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5408-695X","authenticated-orcid":false,"given":"Oluwatobi Sarah","family":"Otun","sequence":"first","affiliation":[{"name":"School of Molecular and Cell Biology, University of the Witwatersrand , Johannesburg 2000 ,","place":["South 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