The main findings of the present study are the following: (i) when compared to healthy controls, dermal fibroblasts from SSc patients display a higher P2X7R surface expression with an enhanced function in terms of Ca2+ influx; (ii) in LPS-primed SSc fibroblasts, P2X7R stimulation results in profibrotic effects by promoting enhanced αSMA expression, cell migration, CTGF, and collagen production; (iii) intracellular mechanisms underlying P2X7R-induced fibrogenic effects seem to involve a cytokine-independent pathway likely due to ERK-1/2 signaling activation. Here, MAPK3 is linked to systemic sclerosis.