DNAJC3 encodes a heat shock protein 40 (Hsp40) family co-chaperone that functions as a critical regulator of endoplasmic reticulum (ER) stress responses. As a co-chaperone of BiP/HSPA5, DNAJC3 stimulates BiP's ATPase activity to facilitate proper protein folding in the ER 1. During ER stress, DNAJC3 acts as a negative regulator of eIF2-alpha kinases (GCN2, PKR, and PERK), preventing excessive phosphorylation of eIF2-alpha and attenuating translation shutdown 2. DNAJC3 also helps maintain functional phase states of nucleolar prion-like proteins through buffering mechanisms 3. Loss-of-function DNAJC3 mutations cause a monogenic recessive syndrome combining early-onset diabetes mellitus with multisystemic neurodegeneration 1. Affected individuals present with juvenile-onset diabetes, ataxia, peripheral neuropathy, sensorineural hearing loss, and cerebral atrophy 12. Mechanistically, DNAJC3 deficiency impairs ER calcium homeostasis via disrupted Sec61 channel gating, triggering beta-cell dysfunction and hyperinsulinemic hypoglycemia in infants that may progress to hyperglycemia 4. Conversely, the antisense lncRNA DNAJC3-AS1 is upregulated in multiple cancers (osteosarcoma, renal cell carcinoma, thyroid carcinoma, colon cancer), promoting tumor progression through microRNA sponging mechanisms 5678. Clinically, DNAJC3 genetic testing is warranted in syndromic diabetes with neurodegeneration or congenital hyperinsulinism.