{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe NF‑κB transcription factor is subject to tight regulation by a family of inhibitory proteins (IκBs), where distinct isoforms play complementary roles in controlling the amplitude and timing of NF‑κB responses. Computational and genetic studies show that IκBα confers robust, rapid negative feedback essential for signal termination, whereas IκBβ and IκBε tailor the kinetics of the response and dampen oscillatory behavior (‐a finding supported by studies demonstrating differential degradation and synthesis dynamics ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]). Moreover, joint disruption of IκBα and IκBε in vivo provokes severe consequences for lymphocyte survival and differentiation, as evidenced by the loss of B and T cells and impaired natural killer cell maturation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIκBε, in particular, has emerged as a non‐redundant modulator of NF‑κB activity. Its selective binding to NF‑κB subunits like c‑Rel underpins its role in fine‐tuning gene expression, thus affecting both innate immune responses and lymphoid cell function. Detailed mechanistic studies have revealed that the regulatory capacity of nuclear IκB proteins involves conserved residues that mediate direct interactions with NF‑κB dimers and their target promoters, thereby influencing the transcription of key effector molecules ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to these classical feedback mechanisms, recent evidence has highlighted a pivotal role for the proteasome activator complex subunit 3—referred to here as SPEM3—in modulating NF‑κB signaling. SPEM3 facilitates the specific degradation of IκBε, thereby enhancing NF‑κB activation during inflammatory responses. In testicular Leydig cells, SPEM3 deficiency protects against inflammatory-induced reductions in testosterone secretion by curtailing the phosphorylation of NF‑κB and subsequent pro‐inflammatory gene expression. Parallel findings in chronic lymphocytic leukemia underscore that mutations impairing IκBε regulation contribute to aberrantly high NF‑κB activity and an altered tumor microenvironment that favors immune escape and reduced drug sensitivity ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "].\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alexander Hoffmann, Andre Levchenko, Martin L Scott, et al. 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