Novel Tetrahydroxanthylium-Based Ligands Targeting Mitochondrial DNA G‑Quadruplex Structures for Concurrent Induction of Apoptosis and Inhibition of Autophagy in Liver Cancer

Liver cancer, a leading cause of
cancer-related mortality, is characterized
by intrinsic and acquired therapeutic resistance linked to dysregulated
programmed cell death pathways. Apoptosis evasion, driven by p53 mutations
or antiapoptotic protein overexpression, and autophagy upregulation,
which sustains cancer cell survival under stress, are critical barriers
to effective treatment. This study introduced XAN-5,
a novel mitochondrial DNA G-quadruplex (mtG4)-targeting tetrahydroxanthylium
ligand that can simultaneously induce apoptosis and inhibit autophagy.
Mechanistically, XAN-5 bound mtG4s, triggering mitochondrial
dysfunction, reactive oxygen species overproduction, and caspase-dependent
apoptosis. Concurrently, XAN-5 disrupted autophagic flux,
evidenced by reduced LC3B–II conversion and p62 accumulation.
In a mouse liver cancer model, XAN-5 inhibited tumor
growth while enhancing tumor-infiltrating CD4+ and CD8+ T cells. These findings highlighted the unique capacity of XAN-5 to target two resistance mechanisms, offering a paradigm
shift in liver cancer therapy.