Na Ji

Immune-mediated necrotizing myopathy (IMNM) is a distinct subtype of idiopathic inflammatory myopathies (IIMs), classified by serum autoantibody status into anti-signal recognition particle (anti-SRP)-positive, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR)-positive, and seronegative subgroups. Its hallmark is a pathological paradox: extensive myofiber necrosis and regeneration accompanied by strikingly sparse inflammatory infiltrates, a feature that distinguishes IMNM from dermatomyositis and inclusion body myositis. In this review, we integrate preclinical and clinical evidence to build an immune-mechanistic pathogenesis model grounded in pathological observations: anti-SRP and anti-HMGCR autoantibodies trigger myofiber injury via both complement-dependent and complement-independent pathways; necrotic myofibers release damage-associated molecular patterns (DAMPs) that activate Toll-like receptor signaling, thereby establishing a complement-independent, self-perpetuating injury-amplification loop; T-cell-dominated adaptive-immune responses, characterized by Th1-M1 pathway activation alongside widespread T-cell exhaustion, may only function as a secondary modulator; and aberrant vascular remodeling coupled with impaired tissue regeneration contributes to long-term prognosis. Variations in macrophage polarization, angiogenic potential, and malignancy risk between anti-SRP-positive and anti-HMGCR-positive IMNM may constitute intrinsic drivers underlying their disparate histopathological features, clinical trajectories, and treatment responses. This model accounts for the limited therapeutic benefit observed with complement-blockade monotherapy and proposes that regimens combining autoantibody suppression with the inhibition of necrosis-driven injury amplification could yield improved clinical outcomes, providing a theoretical basis for pathological subtyping and stratified therapy in IMNM.

Considering the potential links between breast cancer (BC), selective estrogen receptor modulators, and meningioma in previous epidemiology studies, this study aimed to investigate them through the Mendelian randomization approach. We extracted instrumental variables (IVs) of different subtypes of BC from the largest genome-wide association study. Gene targets of SERMs were obtained from the Drug–Gene Interaction Database. Mendelian randomization (MR) analysis applied inverse variance weighted approach to evaluate causality. A series of sensitivity analyses and reverse MR were used to evaluate the stability of the MR results. Genetically determined estrogen receptor (ER) positive BC, luminal A-like breast cancer (OR 1.17, 95% CI 1.04 to 1.32, p = 0.01), and luminal B-like breast cancer (OR 1.20, 95% CI 1.04 to 1.37, p = 0.009) were associated with an increased odds ratio of meningioma (OR 1.18, 95% CI 1.05 to 1.32, p = 0.005). Among SERM-targeted genes, CYP2D6 (OR 1.37, 95% CI 1.23 to 1.54, p = 4.15 × 10^{− 8}), NGR1 (OR 1.15, 95% CI 1.10 to 1.20, p = 2.59 × 10^{− 11}), and MAPT (OR 10.20, 95% CI 2.90 to 35.84, p = 0.0003) were associated with increased meningioma risk, while BRCA1 (OR 0.67, 95% CI 0.57 to 0.80, p = 4.88 × 10^{− 6}) showed negative causal association with meningioma risk. The outcome of the sensitivity analysis and reverse MR analysis corroborated the findings. These findings suggested a causal relationship between BC and meningioma, and identified potential target genes associated with meningioma, which was beneficial to early identification and prevention of meningioma risk.