Objective <p>This study explored the effects of inflammatory microenvironment on stem cells from the apical papilla (SCAP) for cell homing strategy-based pulp regeneration.</p> Methods <p>Dental pulp stem cells (DPSCs) were treated with lipopolysaccharide (LPS) for 48&#xa0;h, creating a conditioned medium (LPS-CM). The influence of LPS-CM on SCAP proliferation, migration, odontogenic and neurogenic differentiation, pro-angiogenetic effects, cell apoptosis and senescence were assessed. Following construction of the ectopic pulp regeneration model, treated dentin matrix (TDM) specimens were harvested after a 2-month implantation period and subjected to histological examination to assess changes in the regenerated tissues.</p> Results <p>We found that a moderate inflammatory microenvironment (LPS-5 CM) significantly enhanced SCAP proliferation, migration, odontogenic differentiation, and the formation of neuron-like cells. In contrast, a high-inflammatory microenvironment (LPS-10 CM) exerted inhibitory effects on these processes and concurrently induced cellular apoptosis and senescence. All LPS-CM groups promoted angiogenesis in vitro. Critically, only the LPS-5 CM group successfully facilitated the regeneration of well-vascularized pulp-like tissue in vivo. </p> Conclusions <p>Inflammatory microenvironment performed a dual role in pulp regeneration. A moderate inflammatory stimulus enhances the regenerative functions of SCAP, while excessive inflammation is detrimental. This underscores the importance of inflammatory signals for successful cell homing-based pulp regeneration.</p> Graphical abstract <p></p>