MZB1 at the ER-immunity interface: from antibody folding to disease vulnerability in autoimmunity, inflammation, and cancer

MZB1 (marginal zone B and B1 cell-specific protein 1) is an endoplasmic reticulum-resident molecular chaperone that is predominantly expressed in marginal zone B cells, B1 cells, plasma cells, and pDCs. Functioning as a co-chaperone of GRP94 and BiP, MZB1 selectively facilitates the proper folding and secretion of immunoglobulin M (IgM) and J-chain-containing immunoglobulin A (IgA) dimers, and maintains the homeostasis of highly secretory cells by upregulating the expression of partner proteins such as BiP/GRP94. This review highlights the emerging role of MZB1 across various pathological conditions. In autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), MZB1 contributes to aberrant autoantibody and cytokine secretion. MZB1 also modulates inflammatory responses in conditions such as colitis and periodontitis by regulating the B cell-skewed inflammatory microenvironment. In oncology, MZB1 is overexpressed in breast cancer (BC), lymphoma, and multiple myeloma (MM), where it is associated with enhanced tumor cell proliferation and poor prognosis. Conversely, in hepatocellular carcinoma (HCC) and gastric cancer (GC), MZB1 is transcriptionally silenced due to promoter hypermethylation. In summary, the tissue-specific expression pattern of MZB1 endows it with potential as both a diagnostic biomarker and therapeutic target, holding significant implications for the exploration of future cancer prognosis and treatment strategies.