2. Academic Validation
  3. Homoharringtonine inhibits growth and migration in non-small cell lung cancer via PDIA4-mediated modulation of autophagy and EMT

Homoharringtonine inhibits growth and migration in non-small cell lung cancer via PDIA4-mediated modulation of autophagy and EMT

  • Arch Pharm Res. 2026 Mar;49(3):357-374. doi: 10.1007/s12272-026-01605-0.
Xiaoyu Ma # 1 2,  Panpan Lei # 1 2,  Bingxi Ren # 1 2,  Sifan Xie 1 2,  Yuxiu Zhang 1 2,  Yuanji Wang 3,  Weina Ma 4 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.
  • 2 State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, 710061, China.
  • 3 Department of Pharmacy, The First Affiliated Hospital of Northwest University, Xi'an, 710002, China.
  • 4 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China. [email protected].
  • 5 State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, 710061, China. [email protected].
  • # Contributed equally.
PMID: 41826608 DOI: 10.1007/s12272-026-01605-0
Abstract

Protein disulfide isomerase A4 (PDIA4) is overexpressed in non-small cell lung Cancer (NSCLC) and is associated with poor prognosis. This study demonstrates that elevated PDIA4 expression promotes NSCLC progression, whereas its knockdown inhibits disease advancement, establishing PDIA4 as an oncogenic driver and potential biomarker. Homoharringtonine (HHT), a natural alkaloid with broad-spectrum antitumor activity, exhibits efficacy against NSCLC, but its underlying mechanism remains unclear. In this study, HHT markedly suppresses NSCLC growth and migration in a PDIA4-dependent manner. Mechanistically, HHT initiates Autophagy by regulating the AMPK/mTOR signaling pathway, while blocking autophagic flux, leading to autophagosome accumulation and consequent inhibition of NSCLC growth. Additionally, HHT inhibits NSCLC migration by modulating epithelial-mesenchymal transition (EMT) signaling. These findings highlight PDIA4 as a critical mediator of HHT efficacy against NSCLC, provide novel insights into PDIA4-associated therapy, and support the translational potential of HHT in NSCLC treatment.

Keywords

Autophagy; Epithelial-mesenchymal transition; Homoharringtonine; Non-small cell lung cancer; Protein disulfide isomerase A4.

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