Dasgupta Sanjukta, Ghosh Moupiya, Chakrabarty Subhendu, Chakrabarti Gopal, Das Amlan
Department of Biotechnology, Center for Multidisciplinary Research & Innovations, Brainware University, 398, Ramkrishnapur Rd, near Jagadighata Market, Barasat, Kolkat, West Bengal , 700125, India.
Department of Basic Science and Humanities, Institute of Engineering and Management (IEM), Kolkata, University of Engineering and Management, Newtown, Kolkata, West Bengal , 700160, India.
Hereditas. 2025 Aug 12;162(1):155. doi: 10.1186/s41065-025-00503-7.
Sarcoidosis patients exhibit an elevated risk of developing lung cancer (LC), suggesting shared genetic and molecular mechanisms between these conditions. This study aimed to identify common differentially expressed genes (DEGs) in sarcoidosis and LC and to evaluate the therapeutic potential of a repurposable drug targeting these shared genes. Gene expression datasets (GSE157671 and GSE229253) were analyzed to identify overlapping DEGs, with validation performed using additional GEO datasets and the GEPIA tool. Functional enrichment and protein-protein interaction (PPI) analyses were conducted using Enrichr and STRING, while associated miRNAs and transcription factors were identified via miRNet. Twelve DEGs-SALL4, WNT10A, RASAL1, CAMK2B, GADD45B, KLF4, OLR1, CSF3, WIF1, RAMP3, AGER, and PRKAG3-were consistently dysregulated in both diseases. These genes were significantly associated with epithelial cell enrichment and the Wnt signaling pathway. Drug-gene interaction analysis using DGIdb prioritized metformin as a candidate drug targeting PRKAG3. Its structural integrity was confirmed via X-ray diffraction (XRD) and Rietveld refinement. In vitro validation using MTT assays revealed that metformin selectively reduced viability in A549 (adenocarcinoma human alveolar basal epithelial cells) and HeLa (a widely used epithelial cancer cell line), with minimal cytotoxicity in WI38 normal lung fibroblasts. Colony formation assays further demonstrated dose-dependent, long-term growth inhibition in cancer cells, corroborated by observable morphological alterations. Overall, this study highlights shared pathogenic signatures between sarcoidosis and LC and proposes metformin as a promising therapeutic candidate. These findings support the rationale for drug repurposing and the development of targeted therapies for patients with overlapping disease profiles or those at increased risk of LC progression from sarcoidosis.
结节病患者患肺癌（LC）的风险升高，这表明这些疾病之间存在共同的遗传和分子机制。本研究旨在确定结节病和肺癌中共同的差异表达基因（DEG），并评估靶向这些共享基因的可重新利用药物的治疗潜力。分析基因表达数据集（GSE157671和GSE229253）以识别重叠的DEG，并使用其他GEO数据集和GEPIA工具进行验证。使用Enrichr和STRING进行功能富集和蛋白质-蛋白质相互作用（PPI）分析，同时通过miRNet识别相关的miRNA和转录因子。十二个DEG——SALL4、WNT10A、RASAL1,、CAMK2B、GADD45B、KLF4、OLR1、CSF3、WIF1、RAMP3、AGER和PRKAG3——在这两种疾病中均持续失调。这些基因与上皮细胞富集和Wnt信号通路显著相关。使用DGIdb进行的药物-基因相互作用分析将二甲双胍列为靶向PRKAG3的候选药物。通过X射线衍射（XRD）和Rietveld精修确认了其结构完整性。使用MTT试验进行的体外验证表明，二甲双胍选择性降低了A549（人肺泡基底上皮腺癌细胞）和HeLa（一种广泛使用的上皮癌细胞系）的活力，对WI38正常肺成纤维细胞的细胞毒性最小。集落形成试验进一步证明了癌细胞中剂量依赖性的长期生长抑制，可观察到的形态学改变证实了这一点。总体而言，本研究突出了结节病和肺癌之间共同的致病特征，并提出二甲双胍是一种有前景的治疗候选药物。这些发现支持了药物重新利用的基本原理，以及为疾病特征重叠或有从结节病进展为肺癌风险增加的患者开发靶向治疗的依据。
