Articles
Vol. 70 No. 2 (2026)
https://doi.org/10.4081/ejh.2026.4544

SUSD2 suppresses lung adenocarcinoma tumorigenesis by inducing autophagy via inhibiting PI3K/AKT/mTOR signaling pathway

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Published: 18 May 2026
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SUSD2, LUAD, autophagy, tumor suppressor, cell proliferation, apoptosis

Authors

Shengwen Wang
Lung Cancer Diagnosis and Treatment, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, China.
Gang Yang
Department of Geriatric Medicine, Wuhu Hospital Affiliated to East China Normal University (Second People's Hospital of Wuhu City), China.
Qian Zhang
Department of Geriatric Medicine, Wuhu Hospital Affiliated to East China Normal University (Second People's Hospital of Wuhu City), China.
Yanbei Zhang
zhangyanbei@ahmu.edu.cn
Lung Cancer Diagnosis and Treatment, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, China.

Lung adenocarcinoma (LUAD) is the most common and aggressive non-small cell lung cancer with limited therapeutic options. SUSD2 exhibits varying regulatory behaviors in different types of tumors, its role in LUAD remains unclear. This study aims to determine the role of SUSD2 in LUAD and explore the underlying mechanism. Through TCGA database analysis, we discovered that SUSD2 expression is significantly downregulated in LUAD tissues, and its low expression is closely associated with advanced disease stages and poor patient prognosis. Further immunohistochemical validation confirmed reduced SUSD2 expression in clinical samples. Functional assays demonstrated that SUSD2 overexpression markedly inhibits LUAD cell proliferation, migration, and invasion, and also suppresses tumor growth and metastasis in mouse models. Mechanistic studies revealed that SUSD2 overexpression promotes autophagic flux (indicated by increased LC3-II and decreased p62) and suppresses the PI3K/AKT/mTOR signaling pathway. The antitumor effects of SUSD2 were attenuated by the autophagy inhibitor 3-MA or ATG5 knockdown, while reactivation of mTOR reversed SUSD2-induced autophagy and tumor suppression. In summary, SUSD2 functions as a tumor suppressor in LUAD by inducing autophagy and inhibiting the PI3K/AKT/mTOR pathway, suggesting its potential as a therapeutic target and prognostic biomarker.

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1. Luo G, Zhang Y, Rumgay H, Morgan E, Langselius O, Vignat J, et al. Estimated worldwide variation and trends in incidence of lung cancer by histological subtype in 2022 and over time: a population-based study. Lancet Respir Med 2025;13:348-63. DOI: https://doi.org/10.1016/S2213-2600(24)00428-4
2. Fang W, Li X, Wang Q, Meng X, Zheng W, Sun L, et al. Sacituzumab tirumotecan versus docetaxel for previously treated EGFR-mutated advanced non-small cell lung cancer: multicentre, open label, randomised controlled trial. BMJ 2025;389:e085680. DOI: https://doi.org/10.1136/bmj-2025-085680
3. Zhang C, Liu Y, Lu Y, Chen Z, Liu Y, Mao Q, et al. Identification of potential biomarkers for lung adenocarcinoma: a study based on bioinformatics analysis combined with validation experiments. Front Oncol 2024;14:1425895. DOI: https://doi.org/10.3389/fonc.2024.1425895
4. Gómez-Virgilio L, Silva-Lucero MD, Flores-Morelos DS, Gallardo-Nieto J, Lopez-Toledo G, Abarca-Fernandez AM, et al. Autophagy: a key regulator of homeostasis and disease: an overview of molecular mechanisms and modulators. Cells 2022;11. DOI: https://doi.org/10.3390/cells11152262
5. Liu S, Yao S, Yang H, Liu S, Wang Y. Autophagy: Regulator of cell death. Cell Death Dis 2023;14:648. DOI: https://doi.org/10.1038/s41419-023-06154-8
6. Wang S, Long H, Hou L, Feng B, Ma Z, Wu Y, et al. The mitophagy pathway and its implications in human diseases. Signal Transduct Target Ther 2023;8:304. DOI: https://doi.org/10.1038/s41392-023-01503-7
7. Wang Q, Sun Y, Li TY, Auwerx J. Mitophagy in the pathogenesis and management of disease. Cell Res 2026;36:11-37. DOI: https://doi.org/10.1038/s41422-025-01203-7
8. Hennes D, Rosamilia A, Werkmeister JA, Gargett CE, Mukherjee S. Endometrial SUSD2(+) mesenchymal stem/stromal cells in tissue engineering: advances in novel cellular constructs for pelvic organ prolapse. J Pers Med 2021;11:840. DOI: https://doi.org/10.3390/jpm11090840
9. Huang T, Ge S, Huang W, Ma T, Sheng Y, Chen J, et al. AIBP promotes cell proliferation and migration through the ERK1/2-MAPK signaling pathway in hepatocellular carcinoma. Transl Cancer Res 2024;13:4028-41. DOI: https://doi.org/10.21037/tcr-23-2101
10. Bai H, Xian N, Zhao F, Zhou Y, Qin S. The dual role of SUSD2 in cancer development. Eur J Pharmacol 2024;977:176754. DOI: https://doi.org/10.1016/j.ejphar.2024.176754
11. Wang F, Li Q, Xie C, Zhu N, Deng Y, Li Y, et al. Dysregulation of SUSD2-CLDN18.2-mediated cell adhesion contributes to lung adenocarcinoma progression associated with chronic low-dose nanoplastics exposure. Ecotoxicol Environ Saf 2025;303:118946. DOI: https://doi.org/10.1016/j.ecoenv.2025.118946
12. Kuo WT, Lee YC, Yang YF, Cheng CF, Tseng CJ, Tsai KW. Sushi Domain Containing 2 dysfunction contributes to cancer progression in patients with bladder cancer. J Cancer 2024;15:5318-28. DOI: https://doi.org/10.7150/jca.97537
13. Liu J, Tao M, Zhao W, Song Q, Yang X, Li M, et al. Calcium channel α2δ1 is essential for pancreatic tumor-initiating cells through sequential phosphorylation of PKM2. Cell Mol Gastroenterol Hepatol 2023;15: 373-392. DOI: https://doi.org/10.1016/j.jcmgh.2022.10.006
14. Tian Y, Xu L, Li X, Li H, Zhao M. SMARCA4: Current status and future perspectives in non-small-cell lung cancer. Cancer Lett 2023;554:216022. DOI: https://doi.org/10.1016/j.canlet.2022.216022
15. Chen P, Quan Z, Song X, Gao Z, Yuan K. MDFI is a novel biomarker for poor prognosis in LUAD. Front Oncol 2022;12:1005962. DOI: https://doi.org/10.3389/fonc.2022.1005962
16. Zhang H, Zhang P, Lin X, Tan L, Wang Y, Jia X, et al. Integrative single-cell analysis of LUAD: elucidating immune cell dynamics and prognostic modeling based on exhausted CD8+ T cells. Front Immunol 2024;15:1366096. DOI: https://doi.org/10.3389/fimmu.2024.1366096
17. Chen JW, Dhahbi J. Lung adenocarcinoma and lung squamous cell carcinoma cancer classification, biomarker identification, and gene expression analysis using overlapping feature selection methods. Sci Rep 2021;11:13323. DOI: https://doi.org/10.1038/s41598-021-92725-8
18. Liu S, Wen C. miR-141-3p promotes retinoblastoma progression via inhibiting sushi domain-containing protein 2. Bioengineered 2022;13:7410-24. DOI: https://doi.org/10.1080/21655979.2022.2048770
19. Yang C, Zhang J, Ding M, Xu K, Li L, Mao L, et al. Ki67 targeted strategies for cancer therapy. Clin Transl Oncol 2018;20:570-5. DOI: https://doi.org/10.1007/s12094-017-1774-3
20. Zhang A, Wang X, Fan C, Mao X. The role of Ki67 in evaluating neoadjuvant endocrine therapy of hormone receptor-positive breast cancer. Front Endocrinol (Lausanne) 2021;12:687244. DOI: https://doi.org/10.3389/fendo.2021.687244
21. Zhou D, Zhang J, Deng X, Lu X, Liu X, Yu J, et al. SUSD2 hypersialylation promotes early lung adenocarcinoma progression by driving ECM remodeling and pro-tumorigenic fibroblast activation. Cancer Lett 2025;633:217995. DOI: https://doi.org/10.1016/j.canlet.2025.217995
22. Moreno-Sanchez PM, Scafidi A, Salvato I. SUSD2-IL-2 receptor interaction hinders antitumoral CD8(+) T-cell activity: Implications for cancer immunotherapy. Allergy 2023;78:3035-7. DOI: https://doi.org/10.1111/all.15804
23. Liu WJ, Ye L, Huang WF, Guo LJ, Xu ZG, Wu HL, et al. p62 links the autophagy pathway and the ubiquitin-proteasome system upon ubiquitinated protein degradation. Cell Mol Biol Lett 2016;21:29. DOI: https://doi.org/10.1186/s11658-016-0031-z
24. Prerna K, Dubey VK. Beclin1-mediated interplay between autophagy and apoptosis: New understanding. Int J Biol Macromol 2022;204:258-73. DOI: https://doi.org/10.1016/j.ijbiomac.2022.02.005
25. Bartkowiak K, Mohammadi PM, Nissen P, Werner S, Agorku D, Andreas A, et al. Discovery of a sushi domain-containing protein 2-positive phenotype in circulating tumor cells of metastatic breast cancer patients. Sci Rep 2025;15:3913. DOI: https://doi.org/10.1038/s41598-025-87122-4
26. Sun X, Meng H, Xiao J, Liu F, Du J, Zeng H. Pretreatment of 3-MA prevents doxorubicin-induced cardiotoxicity through inhibition of autophagy initiation. Toxicology 2023;490:153512. DOI: https://doi.org/10.1016/j.tox.2023.153512
27. Peng Y, Wang Y, Zhou C, Mei W, Zeng C. PI3K/Akt/mTOR pathway and its role in cancer therapeutics: are we making headway? Front Oncol 2022;12:819128. DOI: https://doi.org/10.3389/fonc.2022.819128
28. Mondal K, Posa MK, Shenoy RP, Roychoudhury S. KRAS mutation subtypes and their association with other driver mutations in oncogenic pathways. Cells 2024;13. DOI: https://doi.org/10.3390/cells13141221
29. Alves CL, Ditzel HJ. Drugging the PI3K/AKT/mTOR pathway in ER+ breast cancer. Int J Mol Sci 2023;24. DOI: https://doi.org/10.3390/ijms24054522
30. Zhang J, Li MY, Lu X, Liu QX, Zhou D, Yang GX, et al. CWHM-1008 induces apoptosis and protective autophagy through the Akt/mTOR axis in LUAD cells. J Oncol 2021;2021:5548128. DOI: https://doi.org/10.1155/2021/5548128
31. Li X, He S, Ma B. Autophagy and autophagy-related proteins in cancer. Mol Cancer 2020;19:12. DOI: https://doi.org/10.1186/s12943-020-1138-4
32. Sun K, Luo J, Guo J, Yao X, Jing X, Guo F. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthritis Cartilage 2020;28:400-9. DOI: https://doi.org/10.1016/j.joca.2020.02.027
33. Leiphrakpam PD, Are C. PI3K/Akt/mTOR signaling pathway as a target for colorectal cancer treatment. Int J Mol Sci 2024;25. DOI: https://doi.org/10.3390/ijms25063178
34. Yoshida J, Ohishi T, Momose I, Ohba SI, Kurosawa K, Harakawa A, et al. SUSD2 promotes metastasis and primary tumor growth in pancreatic cancer cells via integrin-FAK signaling activation. Cancer Sci 2026;117:711-26. DOI: https://doi.org/10.1111/cas.70318
35. Gorsek Sparovec T, Markert UR, Reif P, Schoell W, Moser G, Feichtinger J, et al. The fate of human SUSD2+ endometrial mesenchymal stem cells during decidualization. Stem Cell Res 2022;60:102671. DOI: https://doi.org/10.1016/j.scr.2022.102671
36. Zhao B, Gong W, Ma A, Chen J, Velegraki M, Dong H, et al. SUSD2 suppresses CD8(+) T cell antitumor immunity by targeting IL-2 receptor signaling. Nat Immunol 2022;23:1588-99. DOI: https://doi.org/10.1038/s41590-022-01326-8
37. Wei X, Li X, Hu S, Cheng J, Cai R. Regulation of ferroptosis in lung adenocarcinoma. Int J Mol Sci 2023;24. DOI: https://doi.org/10.20944/preprints202309.0765.v1
38. Jiang M, Zhou X, Feng Y, Ding P, Li J, Lu D, et al. DNMT3a promotes LUAD cell proliferation and metastasis by activating the HDAC7 signalling pathway. Int J Biol Sci 2025;21:1585-602. DOI: https://doi.org/10.7150/ijbs.96509
39. Khanmohammadi M, Mukherjee S, Darzi S, Paul K, Werkmeister JA, Cousins FL, et al. Identification and characterisation of maternal perivascular SUSD2(+) placental mesenchymal stem/stromal cells. Cell Tissue Res 2021;385:803-15. DOI: https://doi.org/10.1007/s00441-021-03453-4
40. Wu Y, Duan Y, Li X, Zhao R, Lan B, Zhang X, et al. CBX8 together with SET facilitates ovarian carcinoma growth and metastasis by suppressing the transcription of SUSD2. Mol Cancer Res 2022;20:1611-22. DOI: https://doi.org/10.1158/1541-7786.MCR-22-0139
41. Zhang L, Xiong Y, Zhang J, Feng Y, Xu A. Systematic proteome-wide Mendelian randomization using the human plasma proteome to identify therapeutic targets for lung adenocarcinoma. J Transl Med 2024;22:330. DOI: https://doi.org/10.1186/s12967-024-04919-z
42. Hao C, Wei Y, Meng W, Zhang J, Yang X. PI3K/AKT/mTOR inhibitors for hormone receptor-positive advanced breast cancer. Cancer Treat Rev 2025;132:102861. DOI: https://doi.org/10.1016/j.ctrv.2024.102861
43. Zhang L, Cui Y, Zhou G, Zhang Z, Zhang P. Leveraging mitochondrial-programmed cell death dynamics to enhance prognostic accuracy and immunotherapy efficacy in lung adenocarcinoma. J Immunother Cancer 2024;12:e010008. DOI: https://doi.org/10.1136/jitc-2024-010008

Ethics Approval

This study was approved by the Ethics Committee of Wuhu Second People's Hospital , All animal experiments were approved by the IACUC of Wuhu Second People's Hospital

CRediT authorship contribution

Shengwen Wang, cell-based experiments, animal experiments, experimental datasets validation, writing – original drafting. Gang Yang, bioinformatic analysis. Qian Zhang, immunohistochemistry analysis of clinical lung adenocarcinoma specimens, downstream signaling pathway validation. Yanbei Zhang, experimental protocols design, quality assurance procedures standardization. All the authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

Supporting Agencies

2021 Anhui Provincial Key Medical and Health Specialty Construction Project, 2021 Wuhu Huatuo Plan Project

Data Availability Statement

All data generated or analyzed during this study are included in this published article.

How to Cite



1.
Wang S, Yang G, Zhang Q, Zhang Y. SUSD2 suppresses lung adenocarcinoma tumorigenesis by inducing autophagy via inhibiting PI3K/AKT/mTOR signaling pathway. Eur J Histochem [Internet]. 2026 May 18 [cited 2026 May 18];70(2). Available from: https://www.ejh.it/ejh/article/view/4544
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