Indole-benzimidazole hybrids modulate lipid metabolism and promote autophagic and apoptotic signaling in breast cancer.

Lipid metabolic reprogramming is a hallmark of breast cancer, enabling tumor cells to sustain proliferation, adapt to metabolic stress, and develop therapeutic resistance. Consequently, targeting lipid metabolism has emerged as a promising pharmacological strategy for cancer treatment. In the present study, we investigated the anticancer effects of two novel indole-benzimidazole hybrid compounds, IBB-6 and IBB-7, in MCF-7 and MDA-MB-231 breast cancer cells, with a particular focus on lipid droplet homeostasis and its associated regulatory pathways. Both compounds exhibited significant dose-dependent cytotoxic activity and markedly reduced lipid droplet accumulation, particularly in MCF-7 cells. Molecular analyses revealed that treatment with IBB-6 and IBB-7 suppressed the expression of key lipogenic regulators, including fatty acid synthase (FASN), SREBP cleavage-activating protein (SCAP), MLXIPL (also known as ChREBP), and sphingosine-1-phosphate receptor 1 (S1P1), indicating a disruption of lipid biosynthesis and metabolic adaptation. In parallel, the compounds modulated autophagy-related pathways, as evidenced by increased expression of LC3, ATG6, and HIF-1α, suggesting activation of cellular stress responses associated with metabolic perturbation. Furthermore, both derivatives promoted a pro-apoptotic transcriptional profile characterized by increased Bax and Caspase-7 expression and reduced Bcl-2 levels, supporting the induction of apoptotic cell death. Collectively, these findings demonstrate that indole-benzimidazole hybrids function as multifunctional modulators of breast cancer cell metabolism by coordinately targeting lipid homeostasis, sphingolipid-associated signaling, autophagic regulation, and apoptosis. The ability of IBB-6 and IBB-7 to impair metabolic adaptability and promote cancer cell death highlights their potential as promising therapeutic candidates for breast cancer treatment and warrants further mechanistic and in vivo investigations.