Inhibiting the miR-511-3p/PTCH1/Hedgehog Axis Alleviates Sepsis-Induced Systemic Inflammation and Acute Liver Injury

Sepsis is a life-threatening syndrome characterized by dysregulated systemic inflammation and multiple organ dysfunction, yet the molecular mechanisms underlying its progression remain incompletely understood. Our previous studies demonstrated that microRNA-511-3p (miR-511-3p) is upregulated in both an experimental sepsis model and patients with sepsis, suggesting its potential role in the pathogenesis of sepsis-associated inflammation. Because patched 1 (PTCH1), a validated target of miR-511-3p, serves as a key negative regulator of hedgehog (HH) signaling, we hypothesized that miR-511-3p promotes inflammatory responses during sepsis by suppressing PTCH1 expression and consequently activating HH signaling. To investigate this mechanism, we examined multiple immune cell populations, including small intestinal epithelial cells (S-IECs), small intestinal lamina propria macrophages (SI-LPMs), and liver macrophages (Liv-Ms), in a lipopolysaccharide (LPS)-induced murine sepsis model, as these cell populations may contribute to both local intestinal and systemic inflammatory responses during sepsis. The systemic administration of a miR-511-3p inhibitor (511-Inh) significantly reduced the expression of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor (TNF), as well as Hedgehog-interacting protein (HHIP), a canonical HH target gene. The inhibition of miR-511-3p restored PTCH1 expression in the intestines, liver, and lung and increased its mRNA levels in S-IECs, SI-LPMs, and Liv-Ms. These changes were accompanied by a reduced expression of HH pathway-related genes. Furthermore, miR-511-3p inhibition attenuated sepsis-induced liver injury, as evidenced by improved histopathological findings and decreased plasma levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). To further determine the contribution of HH signaling to sepsis-associated inflammation, septic mice were treated with vismodegib, a selective inhibitor of smoothened (SMO). The pharmacological inhibition of SMO considerably reduced the expression of Smo, Gli, Hhip, Il6, and Tnf in the small intestine, large intestine, liver, and lung, confirming that aberrant HH pathway activation amplifies inflammatory responses during sepsis. Collectively, these findings suggest that miR-511-3p drives sepsis-associated inflammation, at least in part, by suppressing PTCH1 expression and thereby promoting HH signaling. Conversely, inhibiting miR-511-3p restores PTCH1 expression, dampens HH pathway activity, and mitigates systemic inflammation and sepsis-induced organ injury. Thus, the miR-511-3p/PTCH1/HH signaling axis may represent a promising therapeutic target for sepsis.