Introduction <p>Sjögren disease (SjD) causes salivary hypofunction and ocular dryness. To investigate mechanisms of autoimmunity and salivation, we profiled unstimulated whole saliva from SjD patients and demographically matched controls by 4D-DIA proteomics and untargeted LC–MS/MS metabolomics.</p> Method <p>Unstimulated whole saliva from patients meeting the 2016 ACR–EULAR criteria for SjD and demographically matched controls was profiled by 4D-DIA proteomics and untargeted LC–MS/MS metabolomics. An independent validation cohort (newly diagnosed SjD, <i>n</i> = 24; controls, <i>n</i> = 24) underwent ELISA for salivary ZG16B, a subset provided labial minor salivary gland (LSG) tissue for immunofluorescence (IF).</p> Results <p>Proteomics identified 2032 differentially expressed proteins (1355 up; 677 down). Gene Ontology indicated downregulation of epithelial differentiation, structural maintenance, and epithelial tube formation, while KEGG highlighted enrichment of protein catabolism, immune regulation, and protein processing pathways. ZG16B was significantly reduced in SjD. Metabolomics detected 702 differential metabolites (307 up; 385 down); upregulated pathways involved protein digestion/absorption and multiple amino-acid metabolisms, whereas downregulated pathways mapped to aerobic respiration, suggesting reduced energy production. In validation, salivary ZG16B levels were markedly lower in newly diagnosed SjD than controls, and IF showed absent or sparse ZG16B-positive acinar cells in SjD LSG. Salivary ZG16B correlated positively with tear and salivary flow rates and inversely with focus score (FS).</p> Conclusions <p>Integrated proteo-metabolomic analysis reveals concurrent epithelial injury, immune activation, and compromised energy metabolism in SjD salivary glands. ZG16B downregulation is associated with exocrine dysfunction, supporting ZG16B as a promising noninvasive biomarker for SjD.</p> <p><Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p><b>Key Points</b></p> <p>• <i>Saliva multi-omics reveals epithelial injury, immune activation, and metabolic impairment in SjD.</i></p> <p>• <i>ZG16B is consistently downregulated in saliva and salivary gland epithelium.</i></p> <p>• <i>ZG16B shows high diagnostic accuracy and mirrors gland function/histologic damage.</i></p> <p>• <i>Dysregulated proteasomal and amino-acid pathways link molecular changes to secretory dysfunction.</i></p> </entry> </row> </tbody> </tgroup> </Table></p>