DNAJB1 is an HSP40 co-chaperone that functions as a critical regulator of cellular protein homeostasis and heat shock response. Mechanistically, DNAJB1 interacts with HSP70 to stimulate its ATPase activity and facilitate protein folding of unfolded substrates 12. The protein negatively regulates heat shock-induced HSF1 transcriptional activity during heat shock recovery 3. Beyond canonical chaperone functions, DNAJB1 plays specialized roles in protein quality control: it specifically recognizes oligomeric α-synuclein and recruits multiple HSP70 molecules to amyloid fibrils, enabling their disaggregation through coordinated entropic pulling forces—a mechanism relevant to Parkinson's disease pathology 4. Additionally, DNAJB1 differentially modulates phase separation of disease-related proteins like TDP-43, with effects varying by co-chaperone type 5. Clinically, DNAJB1 gained prominence through its fusion with PRKACA in fibrolamellar hepatocellular carcinoma (FLC), a rare but aggressive liver cancer. The DNAJB1-PRKACA fusion drives FLC through elevated PKA activity and impaired SIK signaling, leading to CRTC2/p300-mediated transcriptional reprogramming 6. Notably, the oncogenic phenotype depends on elevated PKA activity rather than the DNAJB1 domain itself 7. The fusion also disrupts cAMP compartmentation by blocking regulatory subunit phase separation 8. DNAJB1-PRKACA-derived peptides induce durable anti-tumor T cell responses, supporting peptide-based immunotherapy approaches 9. Related PRKACA/B fusions in pancreatobiliary tumors similarly drive oncocytic neoplasm development 10.