<p>Sepsis, a life-threatening syndrome driven by a dysregulated host response to infection, leads to systemic inflammation and multi-organ dysfunction. Despite advancements in supportive care, sepsis remains a significant global health challenge, necessitating innovative approaches to improve outcomes. Proteomic profiling has emerged as a transformative tool, providing detailed insights into the molecular mechanisms underlying sepsis and septic shock. Mass spectrometry-based analyses have identified key proteins such as CD14, lysozyme (LYZ), C1QC, C8A, APOB, ORM1, ApoA1, and ApoE, which are involved in inflammation, immune response, complement activation, and lipid metabolism. These biomarkers may complement traditional diagnostic tools by improving molecular characterization, early risk stratification, and the identification of organ dysfunction trajectories, although their clinical superiority over established diagnostic approaches remains to be validated in larger, multicenter cohorts. While ApoA1 and ApoE have been associated with mortality risk and ApoC3 with potentially protective profiles, these findings remain primarily investigational and require validation before being used to guide individualized therapeutic decisions. Additionally, therapeutic targets such as PRDM16 and AMPK show promise in modulating oxidative stress, inflammation, and metabolic dysregulation, while inflammatory mediators like S100 proteins present actionable pathways for intervention. However, translating these proteomic insights into routine clinical practice remains challenging, requiring further research to validate biomarkers and develop effective delivery systems. These findings support a gradual shift toward precision-oriented sepsis research, although further validation is required before proteomic tools can transform routine clinical management.</p>