Combination Pharmacology for ALS: A Mechanistic Rationale.

Amyotrophic lateral sclerosis (ALS) involves multiple converging pathogenic mechanisms, including glutamate excitotoxicity, oxidative and endoplasmic-reticulum stress, mitochondrial dysfunction, neuroinflammation, iron dysregulation, and altered microRNA processing. Expecting a single pharmacologic intervention to meaningfully alter such a complex disease has proven overly optimistic and is reflected by the modest clinical benefits of approved monotherapies. This review outlines the mechanistic foundation and translational rationale for combination pharmacology in ALS. Drawing from paradigms in oncology, infectious disease, and other neurological disorders, it explores how rational multi-target strategies, whether synergistic, complementary, or pathway-divergent, may better address the multifactorial biology of ALS. The review also discusses recent mechanistic examples and design principles for advancing this therapeutic paradigm.