Empagliflozin Modulates Apoptosis and Autophagy Pathways in Lung Cancer Through Network Pharmacology and In Vitro Analysis.
5 affiliations
- 1Biochemistry Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
- 2Department of Biochemistry, Faculty of Pharmacy, Alsalam University, Kafr El, Egypt.
- 3Pharmacology & Environmental Toxicology, Environmental Studies & Research Institute (ESRI), University of Sadat City, Sadat City, Egypt.
- 4Pharmacology Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
- 5Zoology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt.
Abstract
Lung cancer remains a major cause of cancer-related mortality, highlighting the need for novel therapeutic strategies. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor, has demonstrated emerging anticancer activity; however, its effects on apoptosis-autophagy crosstalk in lung cancer remain incompletely understood. This study investigated the anticancer effects of EMPA and the influence of hydroxychloroquine (HCQ)-mediated autophagy inhibition in A549 and HOP-92 human lung cancer cells. Network pharmacology with explicit database association-score cutoffs, and molecular docking validated by redocking of a co-crystallized reference ligand, were used to identify potential EMPA-associated targets and pathways. Cytotoxicity of EMPA, HCQ, and their combination was evaluated by MTT assay, followed by combination index and Bliss analyses. Cell-cycle distribution and apoptosis were assessed by flow cytometry. Expression of apoptosis- and autophagy-related markers was evaluated by RT-qPCR, cleaved caspase-3 analysis, and Western blotting. Network analysis identified 239 overlapping EMPA-lung cancer targets, of which 46 were retained after applying an Open Targets association-score cutoff of 0.30. Docking, validated by reproducing the erlotinib crystal pose in the EGFR kinase domain (heavy-atom RMSD 1.30 ± 0.02 Å), indicated that EMPA can be accommodated at surface sites of ANXA8 (-7.6 kcal/mol) and the p62/SQSTM1 ZZ domain (-7.0 kcal/mol) and within the ligand-binding pocket of PPARγ (-7.5 kcal/mol; PDB 8BF1, the PPARγ-PGC-1α coactivator complex). EMPA reduced cell viability in both cell lines, with greater sensitivity in A549 cells. Combining EMPA with HCQ markedly reduced IC50 values and demonstrated synergistic interactions at IC50. EMPA altered cell-cycle progression and increased apoptotic cell death, accompanied by enhanced BAX and CASP3 expression and cleaved caspase-3 activation. EMPA increased LC3-II without p62 accumulation, consistent with increased autophagic activity, whereas HCQ-containing treatments induced LC3-II and p62 accumulation and enhanced apoptotic signaling. EMPA exerts antiproliferative and pro-apoptotic effects in lung cancer cells while modulating autophagy. Inhibition of lysosomal autophagic degradation by HCQ enhances EMPA-mediated cytotoxicity and apoptosis, supporting further investigation of this combination as an anticancer strategy.
Related
- Notoginsenoside R1 modulates the ATF4-CHOP-Bcl2 signaling pathway to alleviate mitochondrial stress damage and apoptosis in asthmatic airway epithelial cells
- A family of metabolite damage-control phosphatases modulates ROS-induced autophagy and plant stress resilience
- Contribution of the ROS/IRE1α Signaling Pathway to Arsenic Trioxide-Induced Apoptosis and Autophagy-Associated Responses in BEAS-2B Cells
- Harnessing marine polysaccharides for breast cancer therapy: ulvan synergizes with nano-selenium to induce programmed cell death through dual modulation of autophagy and apoptosis
- The BTB/POZ‐MATH Protein ZmBPM1 Interacts With Autophagy‐related Protein ZmATG6 and Modulates the NLR Protein Rp1‐D21‐Mediated Defense Response in Maize
BibTeX
@article{elfeky2026empagliflozin,
title = {{Empagliflozin Modulates Apoptosis and Autophagy Pathways in Lung Cancer Through Network Pharmacology and In Vitro Analysis.}},
author = {Ola A El-Feky and Sara M Hamouda and Manar Mohammed El Tabaa and Sally E Abu-Risha and Ahmed B M Mehany and Othman F Abdelzaher and Samar A El-Adawy},
journal = {Journal of biochemical and molecular toxicology},
year = {2026},
month = nov,
doi = {10.1002/jbt.71174},
url = {https://europepmc.org/article/MED/42998249},
note = {CC BY},
}
RIS
TY - JOUR
TI - Empagliflozin Modulates Apoptosis and Autophagy Pathways in Lung Cancer Through Network Pharmacology and In Vitro Analysis.
AU - Ola A El-Feky
AU - Sara M Hamouda
AU - Manar Mohammed El Tabaa
AU - Sally E Abu-Risha
AU - Ahmed B M Mehany
AU - Othman F Abdelzaher
AU - Samar A El-Adawy
PY - 2026
DA - 2026/11/01
JO - Journal of biochemical and molecular toxicology
DO - 10.1002/jbt.71174
UR - https://europepmc.org/article/MED/42998249
AB - Lung cancer remains a major cause of cancer-related mortality, highlighting the need for novel therapeutic strategies. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor, has demonstrated emerging anticancer activity; however, its effects on apoptosis-autophagy crosstalk in lung cancer remain incompletely understood. This study investigated the anticancer effects of EMPA and the influence of hydroxychloroquine (HCQ)-mediated autophagy inhibition in A549 and HOP-92 human lung cancer cells. Network pharmacology with explicit database association-score cutoffs, and molecular docking validated by redocking of a co-crystallized reference ligand, were used to identify potential EMPA-associated targets and pathways. Cytotoxicity of EMPA, HCQ, and their combination was evaluated by MTT assay, followed by combination index and Bliss analyses. Cell-cycle distribution and apoptosis were assessed by flow cytometry. Expression of apoptosis- and autophagy-related markers was evaluated by RT-qPCR, cleaved caspase-3 analysis, and Western blotting. Network analysis identified 239 overlapping EMPA-lung cancer targets, of which 46 were retained after applying an Open Targets association-score cutoff of 0.30. Docking, validated by reproducing the erlotinib crystal pose in the EGFR kinase domain (heavy-atom RMSD 1.30 ± 0.02 Å), indicated that EMPA can be accommodated at surface sites of ANXA8 (-7.6 kcal/mol) and the p62/SQSTM1 ZZ domain (-7.0 kcal/mol) and within the ligand-binding pocket of PPARγ (-7.5 kcal/mol; PDB 8BF1, the PPARγ-PGC-1α coactivator complex). EMPA reduced cell viability in both cell lines, with greater sensitivity in A549 cells. Combining EMPA with HCQ markedly reduced IC50 values and demonstrated synergistic interactions at IC50. EMPA altered cell-cycle progression and increased apoptotic cell death, accompanied by enhanced BAX and CASP3 expression and cleaved caspase-3 activation. EMPA increased LC3-II without p62 accumulation, consistent with increased autophagic activity, whereas HCQ-containing treatments induced LC3-II and p62 accumulation and enhanced apoptotic signaling. EMPA exerts antiproliferative and pro-apoptotic effects in lung cancer cells while modulating autophagy. Inhibition of lysosomal autophagic degradation by HCQ enhances EMPA-mediated cytotoxicity and apoptosis, supporting further investigation of this combination as an anticancer strategy.
SN - 1095-6670
SN - 1099-0461
ER -