Berberine-mediated neuroprotection in Alzheimer’s disease through regulation of ferroptosis, autophagy and mitophagy

Alzheimer’s disease (AD) is marked by progressive neuronal deterioration resulting from the convergence of mitochondrial dysfunction, disrupted iron homeostasis, elevated oxidative stress, and compromised cellular quality-control systems. In addition to the well-established roles of amyloid-a accumulation and tau pathology, mounting evidence implicates ferroptosis- an iron-dependent, lipid peroxidation-driven mode of regulated cell death-together with defects in autophagy and mitophagy, as tightly interconnected contributors to neuronal degeneration. Despite increasing recognition of this pathological interplay, therapeutic approaches capable of concurrently targeting these mechanisms remain scarce. Berberine, a naturally occurring isoquinoline alkaloid, has attracted interest as a pleiotropic compound with reported antioxidant, mitochondria-stabilizing, and autophagy-modulatory activities. In the present study, a computational systems biology approach was employed to investigate the interplay between ferroptosis, autophagy, and mitophagy in Alzheimer’s disease. Differentially expressed genes were integrated with curated pathway-specific gene sets to identify key overlapping regulators within the FMA axis. Functional enrichment and network-level analyses revealed that these genes are involved in pathways associated with oxidative stress, mitochondrial quality control, and impaired proteostasis. Furthermore, molecular docking analysis suggested that berberine exhibits favourable binding interactions with selected hub targets, supporting its potential role in modulating interconnected cell death and survival pathways. Collectively, these findings highlight the coordinated dysregulation of the FMA axis in AD and provide a computational basis for exploring multi-target therapeutic strategies.