Society of Diabetic Nephropathy Prevention Journal of Nephropathology 2251-8363 16 1 2027 01 01 Cytokine-driven crosstalk; the role of IL-6, TNF-α, and NF-κB signaling in bridging type 2 diabetes mellitus and multiple myeloma pathogenesis e28769 e28769 10.34172/jnp.28769 EN Maryam Aghabozorgi https://orcid.org/0000-0002-4203-6584 Maryam Dehghani Mobarakeh https://orcid.org/0000-0002-4368-3900 Seyyed Hamidreza Motafakeran https://orcid.org/0009-0003-2719-8862 Ahmadreza Maghsoudi https://orcid.org/0000-0002-0173-1222 Journal Article 10.34172/jnp.28769 2026 08 30 2026 10 08 Type 2 diabetes mellitus (T2DM) and multiple myeloma increasingly share a pathophysiological intersection mediated by chronic, low-grade inflammation. Recent epidemiological evidence suggested that patients with T2DM exhibit an elevated risk of developing multiple myeloma, underscoring the clinical relevance of this molecular interplay. This review considers the cytokine-driven crosstalk wherein interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B (NF-κB) signaling bridge the pathogenesis of both diseases. In T2DM, adipose tissue dysfunction and systemic insulin resistance drive the persistent secretion of pro-inflammatory cytokines, notably IL-6 and TNF-α. These circulating mediators systematically activate the NF-κB transcriptional cascade, establishing a pervasive inflammatory state. In the context of multiple myeloma, this altered systemic milieu profoundly impacts the bone marrow microenvironment. Malignant plasma cells hijack this cytokine network; where, IL-6 acts as a principal autocrine and paracrine growth and survival factor, since TNF-α synergistically amplifies NF-κB activation. This sustained NF-κB signaling upregulates anti-apoptotic genes, promotes angiogenesis, and stimulates osteoclast activity, thereby driving myeloma progression and characteristic bone destruction. Consequently, the NF-κB pathway serves as a critical molecular bridge, translating the metabolic inflammation of T2DM into a permissive, tumor-promoting niche that accelerates multiple myeloma initiation, exacerbates disease course, and fosters therapeutic resistance. The synergistic crosstalk between metabolic dysregulation and hematologic malignancy demonstrates a vicious cycle where diabetic inflammation fuels myeloma pathogenesis, and tumor-derived factors further worsen metabolic homeostasis. Hence, dissecting this IL-6, TNF-α, and NF-κB axis reveals compelling dual-purpose therapeutic opportunities. Targeting these shared inflammatory pathways may simultaneously mitigate diabetic complications and dismantle the cytokine scaffolding that sustains multiple myeloma, offering a novel paradigm for managing patients with this complex comorbid presentation.