Amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive mo
tor neuron loss, currently lacks effective clinical treatments and carries an extremely poor prognosis. Recent ad
vances in understanding ALS pathogenesis have increasingly highlighted the central role of genetic factors—par
ticularly as most prior studies focused on high-penetrance classic genes in familial cases, leaving sporadic ALS
genetic architecture largely unexplained. Risk genes typically represent small-effect genetic variants across the
genome that collectively influence disease susceptibility through polygenic interactions, epigenetic modifica
tions, and gene-environment interplay. Breakthroughs from high-throughput sequencing coupled with
multi-omics technologies have identified dozens of novel ALS risk genes in recent years. Elucidating their func
tional mechanisms could provide crucial molecular evidence for decoding ALS heritability patterns. This review
systematically summarizes molecular regulatory mechanisms of newly discovered ALS risk genes over the past
five years, evaluates their potential roles in core pathogenic pathways, and emphasizes their translational poten
tial as precision therapy targets. By integrating multi-omics datasets with gene editing tools, we aim to acceler
ate clinical translation of these findings—potentially transforming ALS management through personalized medi
cine grounded in genetic insights.
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