Therapeutic Potential of Cucurbitacin I in Colon Adenocarcinoma Is Mediated by Modulation of SDHA Expression.

Colorectal cancer is a prevalent malignancy, with colon adenocarcinoma (COAD) representing its most common histological subtype. Although most stage I patients remain disease-free after treatment, a subset rapidly progresses to advanced disease with markedly reduced survival. Therefore, identifying early molecular warning signals in stage I patients is essential for timely intervention. In this study, integrated datasets from The Cancer Genome Atlas and Genotype-Tissue Expression projects were analysed using the landscape dynamic network biomarker (l-DNB) approach to identify progression biomarkers (PBs) for COAD. Twenty PBs were identified, among which succinate dehydrogenase complex flavoprotein subunit A (SDHA) was selected for further investigation. The L1000CDS2 database was subsequently queried utilizing these identified PBs, identifying Cucurbitacin I (CuI) as a promising therapeutic component against COAD. Molecular docking and molecular dynamics simulations demonstrated stable binding between CuI and SDHA, with a binding energy of -9.44 kcal/mol and an RMSD of 2.0 ± 0.3 Å. Subsequent in vitro experiments demonstrated that CuI treatment upregulated SDHA expression and inhibited activation of the NF-κB pathway. Collectively, these findings suggest that the identified PBs may serve as early-warning indicators for stage I COAD patients and that CuI suppresses COAD cell proliferation, potentially through the SDHA/NF-κB axis, highlighting its promise as a potential therapeutic candidate.