Microcystin-LR drives hepatic meta-inflammation and insulin resistance by hijacking the PP2A-JNK signaling axis

Chronic low-grade inflammation is a pivotal driver of metabolic diseases, yet the environmental triggers that initiate this process are not fully defined. Here, we identify the ubiquitous freshwater cyanotoxin, Microcystin-LR (MC-LR), as a potent inducer of hepatic meta-inflammation and subsequent insulin resistance. We demonstrate that chronic exposure to MC-LR in mice provokes a robust pro-inflammatory state in the liver, characterized by the activation of the NF-κB signaling pathway and elevated production of key cytokines such as TNF-α, IL-1β, and IL-6. This inflammatory milieu was tightly linked to the development of hepatic insulin resistance and impaired systemic glucose homeostasis. Mechanistically, we uncovered that MC-LR disrupts cellular signaling by inhibiting protein phosphatase 2A (PP2A), a critical negative regulator of stress-activated pathways. This inhibition unleashed the c-Jun N-terminal kinase (JNK), a central node in stress and immune responses. Hyperactivated JNK then orchestrated the pathological cascade by not only directly impairing insulin receptor substrate-1 (IRS-1) signaling but also amplifying the NF-κB-driven inflammatory response. Crucially, pharmacological inhibition of JNK with AS601245, or its genetic knockdown, served as a powerful immunopharmacological intervention. This intervention effectively suppressed the MC-LR-induced inflammatory cytokine storm and, consequently, restored insulin sensitivity both in vitro and in vivo. Our findings reveal the PP2A-JNK axis as a core mechanism through which an environmental toxin incites sterile inflammation and metabolic dysfunction, highlighting JNK as a promising therapeutic target for mitigating environment-induced immuno-metabolic disorders.