2. Academic Validation
  3. Non-canonical dihydrolipoyl transacetylase promotes chemotherapy resistance via mitochondrial tetrahydrofolate signaling

Non-canonical dihydrolipoyl transacetylase promotes chemotherapy resistance via mitochondrial tetrahydrofolate signaling

  • Nat Commun. 2025 Oct 8;16(1):8932. doi: 10.1038/s41467-025-63892-3.
Jung Seok Hwang 1,  JiHoon Kang 1,  Jaehyun Kim 1,  Kiyoung Eun 1,  Sophia West 2,  Hannah E Bacho 1,  Vanessa Avalos 1,  Sydney Shuff 1,  Dong M Shin 1,  Nabil F Saba 1,  Kelly R Magliocca 3,  Cheng-Kui Qu 4,  Haian Fu 1 2,  Suresh S Ramalingam 1,  Andrey A Ivanov 2,  Taro Hitosugi 5,  Sumin Kang 6
Affiliations

Affiliations

  • 1 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA, USA.
  • 2 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA.
  • 3 Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
  • 4 Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • 5 Department of Oncology, Division of Oncology Research, Mayo Clinic, Rochester, MN, USA.
  • 6 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA, USA. [email protected].
PMID: 41062483 DOI: 10.1038/s41467-025-63892-3
Abstract

Chemotherapy is often a primary treatment for Cancer. However, resistance leads to therapeutic failure. Acetylation dynamics play important regulatory roles in Cancer cells, but the mechanisms by which acetylation mediates therapy resistance remain poorly understood. Here, using acetylome-focused RNA interference (RNAi) screening, we find that acetylation induced by mitochondrial dihydrolipoyl transacetylase (DLAT), independent of the pyruvate dehydrogenase complex, is pivotal in promoting resistance to chemotherapeutics, such as cisplatin. Mechanistically, DLAT acetylates methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) at lysine 44 and promotes 10-formyl-tetrahydrofolate (10-formyl-THF) and consequent mitochondrially encoded cytochrome c oxidase II (MT-CO2) induction. DLAT signaling is elevated in Cancer patients refractory to chemotherapy or chemoimmunotherapy. A decoy peptide DMp39, designed to target DLAT signaling, effectively sensitizes Cancer cells to cisplatin in patient-derived xenograft models. Collectively, our study reveals the crucial role of DLAT in shaping chemotherapy resistance, which involves an interplay between acetylation signaling and metabolic reprogramming, and offers a unique decoy peptide technology to overcome chemotherapy resistance.

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