Sepsis-associated acute kidney injury (SA-AKI) is a devastating critical care complication, affecting ∼60 % of septic patients and increasing their mortality 2-6-fold (Bouchard et al., 2015). Survivors also face higher risk of chronic kidney disease (Noble et al., 2020), reflecting long-term renal impairment. This underscores limitations in current supportive care (Kounatidis et al., 2024) and urgent need for targeted therapies against SA-AKI's core pathophysiology.

SA-AKI is driven by a multiple pathophysiological network involving hemodynamic disturbance, immune dysregulation, and metabolic reprogramming (Kuwabara et al., 2022). A key initiating event is the activation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS), triggering nuclear factor-κB (NF-κB) signaling and pro-inflammatory cytokines production such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) (Zhu et al., 2022). This disrupts endothelial barrier and drives tubular cell loss via programmed cell death, with necroptosis emerging as a critical mediator (Newton et al., 2024).

Necroptosis is a form of regulated necrosis characterized by cellular swelling, membrane disruption, and release of damage-associated molecular patterns (Yu et al., 2024). In SA-AKI, necroptosis is initiated by TLRs activation and mediated by RIPK3-dependent phosphorylation of mixed lineage kinase domain-like protein (MLKL). Phosphorylated MLKL oligomerizes to form membrane pores, ultimately inducing tubular cell death (Huang et al., 2021). Clinically, RIPK3 expression correlates with severity and mortality in septic patients (Wang et al., 2017). Meanwhile, pharmacological inhibition of necroptosis, such as with necrostatin-1 (Ning et al., 2018) or necrosulfonamide (Mulay et al., 2016), mitigates renal injury and improves survival in experimental models, confirming its therapeutic relevance.

Parallel to inflammation and programmed cell death, SA-AKI features dysregulated cyclic adenosine monophosphate (cAMP) signaling, a central pathway governing cellular homeostasis, metabolism, and immune modulation (Abbad et al., 2024; Raker et al., 2016; Xu et al., 2024). Sepsis reduces intracellular cAMP levels via increased phosphodiesterases (PDEs) activity (Boularan and Gales, 2015), impairing downstream protein kinase A (PKA) and cAMP response element-binding protein (CREB) activation, thereby disrupting the anti-inflammatory function (Raker et al., 2016). Conversely, PDE inhibition restores intracellular cAMP levels, activates PKA (Delrue et al., 2024), and phosphorylates CREB at Ser133 residue. Phosphorylated CREB (pCREB) binds to transcriptional coactivator CREB-binding protein (CBP)/p300 (Bartolotti and Lazarov, 2019; Naqvi et al., 2014), competitively inhibiting NF-κB signaling and pro-inflammatory transcription (Shenkar et al., 2001; Silva-Garcia et al., 2018). Emerging evidence further links cAMP/PKA/CREB activation to necroptosis inhibition. This pathway alleviates sepsis-induced cardiomyopathy by suppressing RIPK3-MLKL signaling, suggesting that a potential cross-talk between cAMP signaling and necroptosis regulation in septic organ injury (Liu et al., 2024; Zhou et al., 2024).

Dipyridamole, a clinically approved PDE inhibitor traditionally utilized for its antithrombotic effects (Figueredo et al., 2014; Riksen et al., 2005), offers a unique opportunity to target cAMP dysregulation in SA-AKI. Beyond antiplatelet activity, it elevates both cyclic nucleotides and interstitial adenosine levels, conferring anti-inflammatory and antioxidant properties (Ciacciarelli et al., 2015). Recent studies have also demonstrated its renoprotective effects in various kidney diseases (Donadio et al., 1984; Elsherbiny et al., 2015; Kano et al., 2003); however, its molecular mechanisms in SA-AKI remain unclear.

To address this gap, we performed transcriptomic sequencing on kidney tissue from LPS-induced SA-AKI mice, aiming to identify critical signaling networks driving SA-AKI progression and explore the therapeutic potential of dipyridamole.