Background and purpose <p>Growing evidence indicates that inflammatory cytokines may influence intervertebral disc degeneration both upstream and downstream. To further explore the upstream and downstream direct causality of inflammatory cytokines in intervertebral disc degeneration, we performed a bidirectional, two-sample Mendelian randomization (MR) study.</p> Methods and results <p>Five MR analysis techniques were used to explore the causal relationship, with a sensitivity analysis validating the results. We examined 91 inflammatory cytokines to assess their impact on intervertebral disc degeneration and identify upstream modulators. Three key regulators were identified: cystatin D(OR, 0.88; CI [0.78-1.00]; <i>P</i> = 0.04), IL-15 receptor subunit alpha (OR, 1.17; CI [1.02–1.34]; <i>P</i> = 0.02), and TNF-related apoptosis-inducing ligand (OR, 0.85; CI [0.75–0.98]; <i>P</i> = 0.02). Additionally, we examined the effects of disc degeneration on inflammatory cytokines to identify downstream effectors influencing disc degeneration. We identified four downstream effectors associated with disc degeneration: IL-13(OR 1.05, CI 1.01–1.10, <i>P</i> = 0.01), IL-2 (OR 0.95, CI 0.91–0.99, <i>P</i> = 0.02), IL-20 receptor subunit alpha (OR, 1.05; CI [1.01–1.09]; <i>P</i> = 0.03), and Thymic stromal lymphopoietin(OR, 1.05; CI [1.00-1.10]; <i>P</i> = 0.02).</p> Conclusion <p>This research identified a causal link between inflammatory cytokines and intervertebral disc degeneration, highlighting Cystatin D, IL-15 receptor subunit alpha, and TNF-related apoptosis-inducing ligand as key regulators, with IL-15 receptor subunit alpha possibly being the primary factor. Our hypothesis proposes that after disc degeneration, increased IL-13 and decreased IL-2 levels might slow disc degeneration and provide a protective response. Conversely, higher levels of IL-20 receptor subunit alpha and thymic stromal lymphopoietin could exacerbate inflammation and accelerate disc degeneration.</p>