Introduction and objectives Staphylococcus aureus causes life-threatening diseases such as pneumonia and osteomyelitis. Trained immunity (TI) enhances the immune response to subsequent unrelated challenges through epigenetic reprogramming of transcriptional pathways and alteration of cell metabolism [1]. Moreover, pathogens activate inflammasomes that trigger protease activation, particularly caspase-1. Caspase-1 proteolytically matures and promotes the secretion of mature IL-1β and IL-18 [2]. Our objectives include investigating the development of TI in non-immune cells, examining interleukin production and epigenetic marks, exploring the involvement of reactive oxygen species (ROS), and comprehending the role of inflammasomes and their effector, caspase-1, in the context of S. aureus infection. Materials and methods We developed an in vitro TI model using human osteoblast-like MG-63 and epithelial lung A549 cells [3]. Techniques employed included microbiology methods of bacterial cultivation, enzyme-linked immunosorbent assay (ELISA), microscopic analysis, and flow cytometry. We investigated the involvement of ROS using the scavenger N-acetylcysteine (NAC) [4]. 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 generated via CRISPR-Cas9 technology [5]. The role of bacterial effectors were analyzed using deletion and complemented phenol-soluble modulins (PSMs) mutants. Results, discussion and conclusion 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 at lysine 27 (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 also elevated IL-6/IL-8 production, accompanied by H3K27 acetylation, suggesting its ability to induce TI [3]. Infected MG-63 cells activated inflammasomes, releasing mature IL-1β, while CASP1−/−MG-63 cells lacked this activation. PSMs were identified as key contributors to inflammasome-related IL-1β production using S. aureus mutants. Additionally, caspase-1 deficiency impaired cell defense, resulting in decreased bacterial clearance in CASP1−/−MG-63 cells [5]. Our results demonstrate two host strategies against S. aureus infection with therapeutic potential and reveal the involvement of non-immune cells in defense response beyond their structural functions and tissue homeostasis maintenance.