Targeting the STING-NFκB Pathway via BTK Inhibition: A Dual-Mechanism Therapeutic Strategy Mitigating Neuronal and Microglial Dysfunction in Amyotrophic Lateral Sclerosis [RNA-seq]

We identified the cGAS-STING-NFκB pathway as a dual therapeutic target that combats both neuronal degeneration and neurotoxic glial activity in ALS. Utilizing SOD1-mutant human iPSC-differentiated motor neurons(hiPSC-MNs) and microglia(hiPSC-MGs), we demonstrated that ALS hiPSC-MGs displayed a pronounced proinflammatory phenotype, characterized by significant inflammatory marker elevation (NLRP3 increased 0.66-fold, secreted IL-1β elevated 2.85-fold compared to controls) and compromised phagocytic capacity (48% reduction in bioparticle uptake).

Concurrently, ALS hiPSC-MNs exhibit DNA damage, activating STING-NFκB signaling and triggering caspase-3-mediated apoptosis. Notably, co-culture experiments revealed that inflammatory hiPSC-MGs substantially increased neuronal apoptosis, indicating a toxic intercellular communication mechanism mediated through STING-NFκB signaling. Pharmacological inhibition of Bruton's tyrosine kinase (BTK) - a critical upstream regulator of STING activation - effectively suppressed this inflammatory cascade.