Licochalcones in Pancreatic Ductal Adenocarcinoma and Type 2 Diabetes Mellitus: Context-Dependent Modulation of Shared Signaling Pathways and an Evidence-Stratified Framework

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (T2DM) share developmental links that are both driven by metabolic dysfunctions, complicating early diagnosis and treatment. This review systematically explores the shared pathogenic mechanisms and molecular pathways between PDAC and T2DM, including chronic inflammation (NF-κB/JNK/NLRP3), insulin resistance (PI3K/Akt), metabolic reprogramming (AMPK/mTOR), and oxidative stress (ROS/Nrf2). Methods: Licochalcones (LCs) are natural chalcone constituents derived from the roots of licorice (Glycyrrhiza Radix). The pharmacological activities of different subtypes of LCs (LCA-LCE) in the aforementioned common pathways have been comprehensively analyzed. Results: A possible bidirectional regulatory ability of LCs is proposed: it can restore insulin signaling in metabolically impaired tissues and inhibit abnormal oncogenic signaling pathways in PDAC. Although there are experimental bases, clinical studies on the comorbidity of PDAC and T2DM are still insufficient. This review evaluates whether the context-dependent effects of LCs reported in metabolic and tumor models provide a mechanistic basis for investigating PDAC–T2DM comorbidity. Conclusions: Direct PDAC findings are distinguished from metabolic evidence and non-PDAC tumor studies, while simultaneous antitumor and metabolic benefits remain a hypothesis requiring validation.