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The rapid progression and the absence of a molecular clock that stages the disease timeline make precise therapeutic interventions highly challenging. In this review, we aim to refine the timeline of sepsis-associated AKI by dissecting key molecular events that drive disease progression and may inform therapeutic strategies. AKI, initiated by microbes or infection mimicry, involves the rapid and simultaneous activation of inflammatory and anti-inflammatory pathways. This energy-intensive response is further fueled by the loss of distinction between self and nonself, leading to excessive antiviral responses mediated by self-derived nucleic acids. The resulting metabolic burden overwhelms cellular functions, triggering the integrated stress response and profound translation shutdown. Although this shutdown response may be necessary for energy preservation and for priming endogenous recovery mechanisms, prolonged inhibition of translation represents a maladaptive feature of septic AKI. Despite these challenges, the kidney exhibits remarkable resilience. Recovery relies on metabolic flexibility and stress-adaptive mechanisms, such as enhanced polyamine biosynthesis and RNA editing. Meanwhile, microbes also demonstrate metabolic adaptability, enabling them to evade host defenses and exploit the host environment. Understanding this dynamic interplay along the timeline of septic AKI is essential for developing rational therapeutic strategies.<\/jats:p>","DOI":"10.1681\/asn.0000000809","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T17:00:10Z","timestamp":1751475610000},"page":"2259-2268","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":24,"title":["Molecular Mechanisms of Sepsis-Associated Acute Kidney Injury"],"prefix":"10.1681","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0446-6575","authenticated-orcid":false,"given":"Takashi","family":"Hato","sequence":"first","affiliation":[{"name":"Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana"},{"name":"Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana"},{"name":"Richard L. 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