TNF and Sepsis: Critically, SMAD7 activation attenuated HIF-1α accumulation and rescued mitochondrial failure independently of GDF15 status.<h4>Conclusion</h4>GDF15 orchestrates sepsis tolerance through the SMAD7-HIF-1α axis, preserving mitochondrial integrity while resolving metabolic-inflammatory dysregulation, notably by suppressing the release of pro-inflammatory cytokines such as TNF-α and IL-6.