DNAJC3 encodes a heat shock protein 40 (Hsp40) co-chaperone that regulates endoplasmic reticulum (ER) stress responses. It acts as a co-factor for BiP (HSPA5), enhancing its ATPase activity and promoting protein folding in the ER. DNAJC3 negatively regulates several ER stress-sensing kinases—including EIF2AK4/GCN2, EIF2AK2/PKR, and EIF2AK3/PERK—thereby attenuating translation during ER stress, hypothermia, and amino acid starvation. Biallelic loss-of-function DNAJC3 mutations cause early-onset diabetes mellitus with multisystemic neurodegeneration 1. Affected individuals present with juvenile-onset diabetes, ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy 1. A novel missense variant was recently identified in a 15-year-old with syndromic diabetes accompanied by short stature and sensorineural hearing loss 2. Early-life hyperinsulinemic hypoglycemia has emerged as a primary manifestation, potentially driven by calcium leakage through the ER Sec61 channel when DNAJC3-mediated gating is disrupted 3. In mice, Dnajc3 modulates axonal regeneration capacity; overexpression increases both the number of regenerating axons and the distance traveled 4. The antisense lncRNA DNAJC3-AS1 promotes tumorigenesis in osteosarcoma, renal cell carcinoma, papillary thyroid carcinoma, and colon cancer, acting through microRNA-mediated pathways 5678.