Overcoming drug resistance and minimizing off-target toxicity remain major challenges in cancer therapy. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target. Natural chalcones exhibit antitumor properties linked to oxidative stress induction, yet efficacy and selectivity are limited. To achieve this, we designed and synthesized a series of novel α-lipoic acid (LA)-conjugated chalcone derivatives with the aim of disrupting redox and iron homeostasis to induce ferroptosis in cancer cells. Here, we report that these conjugates elevate reactive oxygen species (ROS) levels most prominently in T24 bladder cancer cells, compared to other tested cell lines, leading to potent growth inhibition and suppressed migration. Mechanistically, RNA-seq and functional assays reveal that the lead compound CA-LA triggers ferroptosis by dysregulating cellular iron and glutathione metabolism. Our work presents a rational design strategy for redox-directed antitumor agents and identifies LA-chalcone hybrids as promising candidates for selective bladder cancer therapy via ferroptosis induction.

This narrative review aimed to critically synthesize and evaluate the current evidence on the roles of TIR domain-containing adaptor protein in tumorigenesis and cancer progression, with a particular focus on elucidating the underlying inflammatory and immune regulatory mechanisms mediated by toll-like receptor signaling. A targeted literature search of recent studies (2015-2024) was performed using PubMed and Web of Science. Classic foundational publications (1998-2014) were supplemented through reference tracking. We included experimental, cellular, and clinical studies focusing on TIR domain-containing adaptor protein in cancer. The synthesized findings indicate that TIR domain-containing adaptor protein has been implicated in malignant progression in bladder, pancreatic, and gastric cancers by sustaining chronic inflammation and shaping an immunosuppressive tumor microenvironment through the TLR2/4-MyD88-NF-κB/MAPK axis, whereas it may exert homeostatic and protective effects in colorectal cancer. TIR domain-containing adaptor protein activity is tightly regulated by cellular origin, ligand specificity, and epigenetic modifications such as promoter methylation, which are closely associated with cancer risk and disease severity. TIR domain-containing adaptor protein serves as a critical regulator in inflammation-driven tumors with distinct context-dependent functions and represents a promising biomarker and therapeutic target. Further research focusing on its precise regulatory mechanisms and cell-specific targeted strategies will facilitate its clinical translation.