Helicopter pylori (H. Pylori) begins its long-term infection in the stomach, where the immune system responds with local neutrophil, lymphocyte, and macrophage infiltration. H pylori infection is known to cause stomach ulcers, but scientists are still largely in the dark about this critical area of health. We transfected HeLa cells with specific siRNA antagonist bacterial CagA gene or siRNA antagonist autophagy-related Atg12, and then H. Pylori reproduction was monitored. We also looked at proinflammatory cytokine secretion from treated cells to see if there was a link between bacterial CagA, host autophagy, and inflammatory events like tumor necrosis factor-alpha (TNF-) and interleukin-6 (IL-6). When compared to control-transfected cells, our findings revealed previously unnoticed changes in cell morphology, number of survived cells, and lactate dehydrogenase (LDH) production after transfection with siRNA targeting CagA or Atg12. Furthermore, targeting CagA effector and Atg12 successfully disrupts H. pylori reproduction in infected cells, as measured by quantitative real-time PCR of bacterial 16S ribosomal RNA (16S rRNA) (q-RT-PCR). Furthermore, CagA downregulation causes an obvious decrease in Raf-1 gene expression, which is an indicator of Megaton-Activated Protein Kinase (MAPK) signaling in infected cells. Finally, IL-6 and TNF- production was mediated in siRNA-transfected cells that attacked either CagA or Atg12 effectors. In conclusion, these findings suggest that targeting the bacterial CagA effector and/or autophagy-related Atg12 as a potential therapeutic strategy for H. pylori infection could present a novel mechanism to disrupt bacterial replication.