Background <p>Pulpitis, characterized by dental pulp inflammation, significantly impacts oral health, yet its molecular mechanisms remain poorly understood. This study investigated the role of endoplasmic reticulum (ER) stress in pulpitis pathogenesis and explored its therapeutic potential.</p> Methods <p>We examined ER stress markers in human pulpitis specimens and lipopolysaccharide (LPS)-treated human dental pulp stem cells (hDPSCs). Transcriptomic analysis of public datasets (GSE98359) was performed to identify ER stress-related differentially expressed genes (DEGs). The therapeutic efficacy of 4-phenylbutyric acid (4-PBA), an ER stress inhibitor, was evaluated in both in vitro and in vivo pulpitis models.</p> Results <p>Significantly elevated expression of BiP and CHOP was observed in pulpitis specimens and LPS-treated hDPSCs. Bioinformatic analysis identified 19 ER stress-related DEGs in pulpitis, with <i>PMAIP1</i> emerging as central regulators. Pathway analysis revealed significant enrichment in ER stress response, inflammatory signaling, and apoptotic pathways. 4-PBA treatment effectively attenuated both LPS-induced ER stress and inflammatory responses in hDPSCs and experimental pulpitis.</p> Conclusions <p>Our findings establish ER stress as a critical mediator in pulpitis pathogenesis and <i>PMAIP1</i> is identified as a key regulatory hub. The therapeutic efficacy of 4-PBA suggests that targeting ER stress represents a promising strategy for pulpitis treatment.</p> Clinical significance <p>The demonstration of 4-PBA therapeutic efficacy provides a strong foundation for developing novel treatments targeting ER stress in pulpitis.</p>