Staphylococcus aureus causes life-threatening diseases such as pneumonia and osteomyelitis. Pathogens activate inflammasomes that trigger protease activation, particularly caspase-1, which promotes the secretion of mature IL-1β and IL-18. Trained immunity (TI) enhances the immune response to subsequent unrelated challenges through epigenetic reprogramming of transcriptional pathways and alteration of cell metabolism. Our objectives include a comparison of IL-1β production by monocyte–like ThP1 cells vs osteoblast-like MG-63 cells and comprehending the role of inflammasomes effector, caspase-1, investigating the development of TI in non-immune MG-63 and epithelial lung A549 cells, in the context of S. aureus infection. The role of inflammasomes and Caspase-1 was examined by a comparison of MG-63 cells and caspase-1 knock-out CASP1−/−MG-63 cells that were produced using CRISPR-Cas9 technology. We developed an in vitro TI model using MG-63 and A549 cells and investigated the involvement of ROS using the scavenger N-acetylcysteine (NAC). ThP1 cells produced a higher amount of IL-1β compared to MG-63 cells. Infected MG-63 cells release mature IL-1β, while CASP1−/−MG-63 cells didn’t. PSMs were identified as key contributors to IL-1β production using deletion and complemented phenol-soluble modulins (PSMs) S. aureus mutants. Caspase-1 deficiency impaired cell defense, resulting in decreased bacterial clearance in CASP1−/−MG-63 cells. β-glucan training of MG-63 and A549 cells increased IL-6/IL-8 production upon a stimulation with S. aureus. Interleukin production positively correlated with Histone 3 acetylation (H3K27), indicating epigenetic reprogramming. NAC addition, prior to β-glucan training before S. aureus infection, inhibited IL-6/IL-8 production, thereby supporting the involvement of ROS in the induction of TI. Cell exposure to bacterium with probiotic properties, Lactococcus lactis, before S. aureus infection elevated IL-6/IL-8 production, accompanied by H3K27 acetylation, suggesting its ability to induce TI. Our results demonstrate two host strategies against S. aureus infection with therapeutic potential.