Primary Sjögren’s syndrome (pSS) causes salivary gland inflammation and tissue damage. Jianpi Zishen Granules (JPZS), a traditional Chinese medicine formula, is clinically effective for pSS, yet its molecular mechanisms linking metabolic reprogramming to epigenetic modifications remain unclear. This study investigated whether JPZS alleviates pSS by regulating the crosstalk between the gluconeogenic enzyme PCK2 and histone lactylation.

We performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from a 75-subject clinical cohort (healthy controls and pSS patients) combined with clinical correlation analyses. An in vitro model of human salivary gland epithelial cells (HSGECs) stimulated with pSS-derived serum was used. We utilized PCK2 gain-of-function assays, molecular quantification of histone H3 lysine 9 lactylation (H3K9la), and intervention with JPZS-medicated serum. Key endpoints included the evaluation of the PCK2/Lactate/ACSS2/H3K9la axis via RT-qPCR and Western blotting, alongside functional assessments of cellular phenotype.

PCK2 deficiency drives pSS pathogenesis via a dysregulated Lactate-H3K9la-HIF-1α axis. JPZS exerts therapeutic effects by restoring this metabolic-epigenetic homeostasis, offering a novel strategy for resolving salivary gland inflammation. pSS patients exhibited suppressed PCK2 and lactate transporters (SLC16A3/7), concurrent with upregulated ACSS2. This metabolic defect caused intracellular lactate accumulation, driving ACSS2-mediated H3K9la, which stabilized HIF-1α and promoted IL-6 and IL-23A expression. PCK2 deficiency correlated with disease activity (ESSDAI). In HSGECs, JPZS medicated serum restored PCK2 expression, suppressed ACSS2, and reduced H3K9la levels. Functionally, JPZS acted synergistically with PCK2 restoration to inhibit epithelial proliferation and migration while inducing apoptosis.

We identify PCK2 deficiency as a critical driver of pSS pathogenesis. This metabolic defect causes intracellular lactate accumulation, which fuels histone H3K9 lactylation to stabilize HIF-1α and perpetuate inflammation (Figure 11). Furthermore, we demonstrate that JPZS effectively dismantles this axis by restoring PCK2 expression and metabolic flux. This intervention resolves the pathological hyperactivation of salivary gland epithelial cells, suppressing aberrant proliferation while inducing apoptosis to restore tissue homeostasis (Figure 12). Our findings highlight the PCK2-Lactate-H3K9la axis as a novel therapeutic target for immunometabolic reprogramming in pSS.