Intensification versus combination: revisiting the past and envisioning the future of LDHA inhibitors.

Authors

Weixi Yuan, Qiang Kang, Yin Zhao, Zhe Wang, Yujia He, Chengxiao Fu, Hongxiang Xiao, Xiaoyong Lei, Zhizhong Xie, Xiaoyan Yang, Bo Yang, Guotao Tang, Xiangping Deng

Published in

Cancer chemotherapy and pharmacology. Volume 96. Issue 1. Aug 20, 2026. Epub Aug 20, 2026.

Abstract

As a key enzyme in pyruvate metabolism, lactate dehydrogenase A (LDHA) has been extensively studied for its role in cellular energy regulation and disease pathology. Given its central role in the Warburg effect (cancer cells have a higher intensity of glycolysis even under oxygen-rich conditions) cytoplasmic LDHA emerges as a strategic therapeutic target for tumor suppression through glycolytic pathway inhibition. Despite extensive research, the development of effective LDHA inhibitors has seen limited success, highlighting the urgent need to reassess its molecular properties and refine drug design strategies. In this review, we systematically analyze LDHA's structural biology, critically evaluate the strengths and shortcomings of current inhibitors, and propose novel conceptual frameworks for inhibitor development based on recent insights into LDHA-mediated glycolysis reprogramming. By integrating recent insights into LDHA-mediated glycolysis reprogramming, this review lays the groundwork for rational inhibitor design and its clinical application, either as monotherapy or in combination treatments for cancer.

PMID:
42622823
Bibliographic data and abstract were imported from PubMed on 21 Aug 2026.

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