Mechanistic Exploration of Half-Sandwich Iridium(III) Anticancer Compounds through Integrated Cellular, Proteomic, and In Vivo Analyses.

New half-sandwich iridium(III) compounds [Ir(η5-Cpx)Cl(L1-3)]PF6 (1-6), combining Cp* or Cpph with N,P-coordinated phosphinoalkylamines L1-L3, were tested in different cancer cells (2D and 3D cultures), including MOR/CPR cisplatin-resistant lung carcinoma. Best-performing compound 3 outperformed its Cpph analogue 6 and cisplatin in MOR/CPR cells while sparing noncancerous cells. Multiomics profiling shows a non-DNA-targeted mechanism: rapid integrated stress response with ER stress (DDIT3/CHOP) and oxidative stress (HMOX1, ATF3), nucleolar stress, and primary inhibition of ribosome biogenesis and mitochondrial translation. These changes drive translational shutdown, suppression of oxidative phosphorylation with a glycolytic shift, and G1 arrest, alongside endolysosomal remodeling (enhanced vesicular uptake, reduced degradative capacity) that favors intracellular retention. The phenotype is predominantly cytostatic with apoptotic priming. In vivo, 3 suppressed tumor growth and activated apoptosis with low systemic toxicity. Compound 3 thus emerges as a promising prototype Ir(III) metallodrug that disrupts nucleolar, mitochondrial, and lysosomal homeostasis to overcome resistance.