2. Academic Validation
  3. Lactylation of HK2 facilitates cisplatin resistance in NSCLC by promoting cell migration, invasion, and glycolysis

Lactylation of HK2 facilitates cisplatin resistance in NSCLC by promoting cell migration, invasion, and glycolysis

  • Pathol Res Pract. 2025 Dec 29:279:156349. doi: 10.1016/j.prp.2025.156349.
Fanrui Zeng 1,  Wenyang Wang 2,  Peng Liu 3,  Qingsi Zeng 4
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. Electronic address: [email protected].
  • 2 Department of Radiation Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 3 Department of Stomatology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 4 Department of Radiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
PMID: 41499825 DOI: 10.1016/j.prp.2025.156349
Abstract

Objective: Cisplatin (DDP) resistance has markedly diminished the efficacy of DDP-based chemotherapy in non-small cell lung Cancer (NSCLC). Glycolysis represents a key contributor to NSCLC progression. Lactylation, a novel epigenetic modification, directly regulates glycolysis-associated gene expression. This study aimed to investigate whether lactylation-mediated modulation of glycolytic genes contributes to DDP resistance in NSCLC.

Methods: Cell viability, migration, and invasion capacities in parental and resistant NSCLC cells were assessed using cell counting kit-8 and Transwell migration/invasion assays. RT-qPCR and Western blot analyses were employed to quantify mRNA and protein levels of glycolytic markers. A xenografted tumor model was established to evaluate in vivo tumor progression.

Results: DDP-resistant NSCLC cells exhibited elevated glycolysis activity and increased lactylation levels of Hexokinase 2 (HK2). Moreover, HK2 lysine lactylation (Kla) and protein stability were enhanced in resistant cells through suppression of ubiquitination. Functional experiments demonstrated that HK2 downregulation inhibited cell viability, migration, invasion, and glycolytic metabolism in A549/DDP and H1229/DDP cells, with these effects being reversed following sodium lactate treatment. Crucially, the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) abrogated this rescue, and a K873R lactylation-deficient mutant failed to restore the malignant phenotype, confirming the specificity of the mechanism. In vivo studies further confirmed that HK2 inhibition suppressed tumor growth.

Conclusions: Lactylation at K873 stabilized HK2 by inhibiting its ubiquitination, which in turn drove glycolytic flux and promoted malignant behaviors in DDP-resistant NSCLC. This HK2 lactylation-stabilization axis represents a novel mechanism underlying chemoresistance and a promising therapeutic target for overcoming DDP resistance in NSCLC.

Keywords

DDP resistance; Glycolysis; HK2; Invasion; Lactylation; Migration; Non-small cell lung cancer.

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