DNAJA3 is a mitochondrial DnaJ co-chaperone that functions as a critical regulator of cellular homeostasis and immune signaling. Primary Function: DNAJA3 modulates apoptotic pathways by affecting cytochrome C release and caspase 3 activation within the mitochondrial matrix, with isoform-dependent effects where isoform 1 increases apoptosis while isoform 2 suppresses it [UniProt]. Mechanism: DNAJA3 functions as an HSP70 co-chaperone partner to regulate NF-κB signaling during immune responses, with HSPA1A and HSPA8 physically interacting with DNAJA3 to enable NF-κB p65 phosphorylation 1. The protein also regulates MYC turnover through tubulin-dependent mechanisms in B-cell lymphoma 2. Disease Relevance: DNAJA3 haploinsufficiency in skeletal muscle causes sarcopenic obesity through impaired mitochondrial respiration and dysregulated lipid metabolism 3. Reduced DNAJA3 expression (rs3747579-TT variant) associates with NASH-related hepatocellular carcinoma, with hepatocyte-specific Dnaja3 depletion causing spontaneous NASH/HCC development 4. DNAJA3 variants also associate with breast cancer risk independent of known GWAS loci 5. Clinical Significance: DNAJA3 represents a therapeutic target, as activating DNAJA3 via GMI treatment ameliorated sarcopenic obesity and improved metabolic parameters 3. DNAJA3 also antagonizes viral immune evasion in African swine fever infection 6.