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Aim: Senescence of alveolar type II (AT2) cells is an important driver of pulmonary fibrosis. This study aimed to investigate whether and how dysregulation of hydrogen sulfide (H 2 S) production affected AT2 cell senescence, and then explored the effect of H 2 S on the communication between AT2 and fibroblasts., Methods: ICR mice were intratracheally administered with bleomycin (3 mg/kg). Sodium hydrosulfide (NaHS, 28 μmol/kg/d) was intraperitoneally injected for 2 weeks. The H 2 S-generating enzyme cystathionine-β-synthase (CBS) knockout heterozygous (CBS +/- ) mice were used as a low H 2 S production model., Results: Analysis of microarray datasets revealed downregulation of H 2 S-generating enzymes in lung tissues of patients with pulmonary fibrosis. Decreased H 2 S production was correlated with higher levels of cell senescence markers p53 and p21 in bleomycin-induced lung fibrosis. CBS +/- mice exhibited increased levels of p53 and p21. The numbers of AT2 cells positive for p53 and p21 were increased in CBS +/- mice as compared to control mice. H 2 S donor NaHS attenuated bleomycin-induced AT2 cell senescence both in vivo and in vitro. H 2 S donor suppressed bleomycin-induced senescence-associated secretory phenotype (SASP) of AT2 cells via inhibiting p53/p21 pathway, consequently suppressing proliferation and myofibroblast transdifferentiation of fibroblasts. Mechanically, H 2 S suppressed p53 expression by enhancing the mouse double-minute 2 homologue (MDM2)-mediated ubiquitination and degradation of p53., Conclusion: H 2 S inactivated p53-p21 pathway, consequently suppressing AT2 cell senescence as well as cell communication between senescent AT2 cells and fibroblasts. Aberrant H 2 S synthesis may contribute to the development of pulmonary fibrosis through promoting the activation loop involving senescent AT2 cells and activated fibroblasts., (© 2023 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)