Open research questions in NF-κB Signaling Pathways

What the literature leaves open

• Collectively, these findings provide preliminary theoretical evidence for inflammatory responses and post-transcriptional regulatory networks in MIRI, laying a foundation for further research on targeted diagnostic and therapeutic strategies.

  Identification of NF-κB pathway-related biomarkers in myocardial ischemia-reperfusion injury: based on transcriptomics analysis and RT-qPCR validation · 2026 · DOI

• Although direct studies on the role of Nfkbia in MIRI are currently lacking, this gene has been identified as an immune-related hub gene in hepatic ischemia-reperfusion injury, suggesting its regulatory Scientific Reports | (2026) 16:11729 | https://doi.

  Identification of NF-κB pathway-related biomarkers in myocardial ischemia-reperfusion injury: based on transcriptomics analysis and RT-qPCR validation · 2026 · DOI

• After nearly 40 years of research, the study of NF-kB signaling has not only flourished but continues to yield unexpected in cell biology, discoveries. This pathway has proven crucial regulating essential processes such as cell division, apoptosis, senescence, migration and effector function. NF-kB is classically considered a driver of inflammation and organogenesis but, for T lymphocytes, this signaling pathway is also a ruler of their fate. With the advent of new transgenic inducible animal models, previously contentious issues regarding the role of NF-kB in thymic selection, homeostasis, and CD4 T cell differentiation have been revisited. Recent findings have unveiled surprising roles for NF-kB in antitumor T cell responses, experimental autoimmune encephalomyelitis (EAE), and the development of T cell memory during infections. However, a critical question remains: how does the NF-kB signaling network enable T cells to make specific differentiation choices? This may depend on how NF-kB signaling influences T cell epigenetics and metabolism. These areas, alongside NF-kB dynamics, are largely unexplored and require further investigation (Figure 4). Gaining a better understanding of how environmental triggers of NF-kB work during the immune response, along with their mechanisms, is essential and could lead to new therapeutic

  The NF-κB signaling network in the life of T cells · 2025 · DOI

• The breakthrough discovery of MALT1 protease function in 2008 inspired tremendous research on how this intriguing catalytic activity shapes immune responses. Identification of MALT1 substrates and genetic or pharmacologic MALT1 inactivation have been pursued as the two main strategies to decipher the functions of the MALT1 protease. While the discovery of various substrates untangled cellular pathways and processes controlled by MALT1 cleavage activity, its inactivation demonstrated that MALT1 protease is essential for maintaining peripheral immune tolerance and driving the growth of hematologic and non-hematologic cancers. However, in most cases, it is unclear how cleavage of individual substrates contributes to the pathophysiological functions of MALT1. It remains an open question, whether we have identified the majority of MALT1 substrates or if we are still looking at the tip of the iceberg. Initial discoveries of substrates primarily relied on serendipity, but recent bioinformatic-guided substrate discovery has identified and confirmed approximately 20 and predicted about 10 more MALT1 substrates (30). However, the algorithm for predicting MALT1 substrates is also based on protein functions, which may create a bias towards known/expected rather than new/ unexpected substrates. The relatively loose recognition motif (L-X- S/P-R-G) can be found in many proteins, raising questions about how substrates are recognized and where cleavage occurs in a physiological context. Indeed, the shift in substrate selectivity in the oncogenic API2-MALT1 fusion protein exemplifies the importance of molecular context. It will be crucial to study if different CARDs can facilitate recruitment and targeting of unique MALT1 substrates in a stimulus and cell-type-specific manner, for instance by comparing if CARD14 promotes cleavage of other substrates in keratinocytes than CARD11 in lymphocytes. Further, while there is good evidence that substrates like HOIL-1, BCL10 and A20 are recruited to the CBM complex for cleavage, substrates like RBPs have never been detected at the CBM complex. Using chemical probes, it was shown that active MALT1 is not retained at the CBM complex, but we lack tools to monitor the cellular localization of proteolytically active MALT1, which can also be necessary for the selection of substrates (105). Overall, current studies connecting known substrates to MALT1 protease functions must still be complemented by the discovery of new substrates. While initial studies mainly focused on analyzing effects of MALT1 substrate cleavage in a cellular context, more recently, in vivo functions were explored by generating transgenic mice expressing the non- cleavable substrates MALT1 (R149A), HOIL-1 (R165A), Tensin-3 (R614A/R645A) and Roquin-1 (R510/579A). None of these mice spontaneously develop any severe phenotypes. However, Treg cells were mildly decreased in mice expressing cleavage resistant MALT1, correlating with improved anti-tumor immunity (39). Moreover, cleavage resistant Roquin-1 protects mice from EAE and fatal autoimmune inflammation caused by chronic MALT1 protease activation, revealing that continuous Roquin-1 cleavage, just like its complete ablation, triggers autoimmunity (92). These results emphasize that MALT1 acts as a bifurcation point, with its scaffolding and protease functions coordinating gene induction at the transcriptional and post-transcriptional levels, respectively. Overall, inactivation of these substrates alone is not sufficient to phenocopy the severe effects observed in catalytically inactive Malt1 PD mice under steady state conditions. However, the effects of individual substrates can modulate responses to immunological challenges. In the future, it will be interesting to see whether combining multiple uncleavable substrates will also affect immune homeostasis. MALT1 protease is indispensable for Treg cell development and suppressive functions. However, Treg cells provide a paradigm for the difficulties to causally link the effects of the MALT1 protease with the cleavage of specific substrates. Canonical and non- canonical NF-kB activation is required for Treg cell identity and function (106, 107). In addition, CYLD is involved in differentiation of Treg cells (108). Thus, MALT1 cleavage of A20, CYLD or RelB may directly or indirectly enhance NF-kB activation in Treg cells. Alternatively, the atypical IkB protein NFKBID/IkBNS is also

  MALT1 substrate cleavage: what is it good for? · 2024 · DOI

• In any case, this study is one of the few reports on positive regulators of TLR4 signaling; however, a limitation of this study is that the function of LINCR was evaluated only in RAW264. However, there have been few reports on positive regulators that enhance TLR signals.

  The E3 Ubiquitin Protein Ligase LINCR Amplifies the TLR-Mediated Signals through Direct Degradation of MKP1 · 2024 · DOI

• Investigating the cell-specific role of TRAF1 in RA is hindered by the lack of conditional TRAF1 knockout mice, and future studies should focus on generating these mice to confirm these observations in synovial macrophages. The limitations of this study include the injection of bone marrow-derived macrophages into the knee joints. Yet, to our knowledge, no studies have demonstrated a direct involvement of TRAF1 in driving the pathogenesis of RA. While great progress has been made in understanding RA pathogenesis, a cure remains elusive. Further research into the molecular mechanisms driving RA inflammation is vital.

  TRAF1 Deficiency in Macrophages Drives Exacerbated Joint Inflammation in Rheumatoid Arthritis · 2024 · DOI

• Due to variations in gene mutation sites and their impact on different signaling path- ways, the relationship between genotype and phenotype remains unclear.

  Pediatric ectodermal dysplasia with immunodeficiency caused by a hemizygous IKBKG frameshift variant: a case report and literature review · 2026 · DOI

• These studies suggested that m6A modification is involved in renal IRI regulation but this warrants further study.

  Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment · 2023 · DOI

• immunosuppression, Conventional treatments yield inconsistent results much of the time.

  Finally, She Smiled: A Case of Granulomatous Cheilitis Treated with Tofacitinib · 2026 · DOI

• ABSTRACT Excessive inflammatory responses are a primary driver of acute lung injury, yet the underlying molecular mechanisms remain incompletely understood.

  SKP2 Regulates Pulmonary Inflammatory Injury Triggered by Bacterial Infection Through p27‐Mediated Degradation of FOXN3 · 2026 · DOI

• Dysregulated MALT1 signaling has been implicated in multiple autoimmune diseases, yet its role in autoimmune myocarditis remains poorly defined.

  Pharmacological MALT1 inhibition ameliorates cardiac inflammation and dysfunction in experimental autoimmune myocarditis · 2026 · DOI

• However, the genetic mechanisms underlying this disparity remain poorly understood.

  The AGPS regulatory variant rs113671272 confers esophageal squamous cell carcinoma susceptibility through allele-specific MEIS3 binding and NF-κB activation in Chinese populations · 2026 · DOI

• DNA damage selectively induces post-translational modifications at lysine residues 277 and 309 of the human ubiquitin-binding protein NEMO to promote NF-κB signaling, but the physiological importance of these modifications in vivo remains unclear.

  NF-κB/RelA signaling required for CD40-induced humoral immunity depends on specific NEMO lysine residues in mice · 2026 · DOI

• Randall’s plaques (RPs), calcium deposits on renal papillae, act as anchoring sites for CaOx crystal growth, but the cellular origin and immunoregulatory mechanism underlying early calcium deposition remain unclear.

  M2 Macrophages Attenuate AQP2 + Collecting Duct Cell Apoptosis via the TRAF1–TRAF2 Complex to Suppress Randall’s Plaque Formation · 2026 · DOI

• The mechanisms need to be studied comprehensively, and human studies need to be supplemented and improved.

  TNFAIP8L3 regulation of the TGF-β signaling pathway affects the proportion of macrophages during tumor antigen presentation and affects the prognosis of ovarian cancer · 2025 · DOI

• Whether TNFAIP8L3 directly regulates these pathways or is simply related to their activity remains to be fully elucidated.

  TNFAIP8L3 regulation of the TGF-β signaling pathway affects the proportion of macrophages during tumor antigen presentation and affects the prognosis of ovarian cancer · 2025 · DOI

• PTEN‑induced putative kinase 1 (PINK1), a master regulator of mitophagy, is implicated in mitochondrial homeostasis, yet its role in knee osteoarthritis (OA) pathogenesis remains unclear.

  PINK1 overexpression suppresses p38 MAPK/NF‑κB signaling to attenuate chondrocyte senescence in osteoarthritis · 2025 · DOI

• However, the impact of TWEAK on the characteristics of periodontal ligament stem cells (PDLSCs), which subsequently influence periodontal homeostasis, remains inadequately understood.

  TWEAK modulates the characteristics of periodontal ligament stem cells via the Fn14/NF‑κB pathway · 2025 · DOI

• However, the expression and function of P4HA2 in PTC progression have not been well studied.

  P4HA2 promotes the progression of papillary thyroid cancer by enhancing degradation of IκBα to activate NF-κB signaling pathway · 2025 · DOI

• The transcription factor NF-κB plays a central role in coordinating inflammation, but the mechanisms that regulate NF-κB signaling are not fully understood.

  Human OCEL1 senses bacterial infection to unlock inflammatory responses · 2025 · DOI

• Chemoresistance poses a significant clinical challenge in the treatment of gastric cancer (GC), while its underlying molecular mechanisms are still not fully understood.

  Targeting TRAF6/IRF3 axis to inhibit NF-κB-p65 nuclear translocation enhances the chemosensitivity of 5-FU and reverses the proliferation of gastric cancer · 2024 · DOI

• However, the molecular switches that control the pathogenic activation of SFs remain poorly defined.

  Cyld restrains the hyperactivation of synovial fibroblasts in inflammatory arthritis by regulating the TAK1/IKK2 signaling axis · 2024 · DOI

• While various reports have highlighted the importance of NF-κB subunit specificity in the transcription regulation of certain target genes, the dynamic nature of the NF-κB dimer composition is not well understood.

  Biophysical characterization of RelA –p52 NF ‐ κB dimer—A link between the canonical and the non‐canonical NF ‐ κB pathway · 2024 · DOI

• BACKGROUND: Nuclear factor kappa B (NF-κB) c-Rel is a psoriasis susceptibility locus, however mechanisms underlying c-Rel transactivation during disease are poorly understood.

  NF-κB c-Rel is a critical regulator of TLR7-induced inflammation in psoriasis · 2024 · DOI

• However, the molecular mechanisms of TRAF7 in the underlying pathogenesis of pathological cardiac hypertrophy remain unknown.

  Cardiac tumour necrosis factor receptor-associated factor 7 mediates the ubiquitination of apoptosis signal-regulating kinase 1 and aggravates cardiac hypertrophy · 2024 · DOI

Most-cited papers in NF-κB Signaling Pathways

• Mitogen-Activated Protein Kinase Pathways Mediated by ERK, JNK, and p38 Protein Kinases · Science · 2002 · 3,591 citations
• Nuclear factor-κB in cancer development and progression · Nature · 2006 · 3,028 citations
• An Essential Role for NF-κB in Preventing TNF-α-Induced Cell Death · Science · 1996 · 2,584 citations
• NF-κB Antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to Suppress Caspase-8 Activation · Science · 1998 · 2,258 citations
• Suppression of TNF-α-Induced Apoptosis by NF-κB · Science · 1996 · 2,170 citations
• TNF- and Cancer Therapy-Induced Apoptosis: Potentiation by Inhibition of NF-κB · Science · 1996 · 2,133 citations
• NF-κB in biology and targeted therapy: new insights and translational implications · Signal Transduction and Targeted Therapy · 2024 · 1,748 citations
• NF-κB: At the Borders of Autoimmunity and Inflammation · Frontiers in Immunology · 2021 · 618 citations
• NF‐κB signaling in inflammation and cancer · MedComm · 2021 · 570 citations
• Transcription Factor NF‐κB: A Sensor for Smoke and Stress Signals · Annals of the New York Academy of Sciences · 2005 · 372 citations

Most recent work

• The Role of the NF-κB Signaling Pathway in Atherosclerotic Plaque Rupture and Targeted Therapeutic Strategies · Biomedicines · 2026
• Human genetics guides the discovery of CARD9 inhibitors with anti-inflammatory activity · Cell · 2026
• NF-κB-activated fibroblasts orchestrate inflammaging and emergence of pro-inflammatory granzyme K+ T cells · Immunity · 2026
• Harnessing nanomedicine to target NF-κB signalling in cancer: at the intersection of inflammatory signalling, metabolic reprogramming, and therapeutic innovation · Cell Communication and Signaling · 2026
• Targeting NF-κB Signaling with Natural Products: A Promising Therapeutic Strategy for Cardiovascular Diseases · Biomolecules · 2026
• A first-in-kind MAPK13 inhibitor corrects stem cell reprogramming and muco-obstructive lung disease · bioRxiv · 2026
• Dietary Polyphenols as Natural Modulators of NF ‐ κB Signaling in Inflammation‐Driven Non‐Communicable Diseases: Focus on Cancer · Food Science & Nutrition · 2026
• Alveolar epithelial NF-κB/RelA guards the lung against bacterial infection · The Journal of Immunology · 2026
• 7,8-Dihydroxyflavone alleviates ulcerative colitis by binding keap1 to activate an slc7a11-dependent inhibition of NF-κB p65 signaling in macrophages · Journal of Advanced Research · 2026
• USP19 alleviates LPS-induced acute lung injury via inhibiting TAK1 activation · Biology Direct · 2026

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