SEASONAL PM2.5 DIFFERENTIALLY REGULATES JAK2/STAT3 SIGNALING IN RURAL AND URBAN COHORTS

Ghosh, S.; Chaudhuri, R.; Mukherjee, M.; Samanta, A.; Saha, P.; Henneman, L. R.; Majumdar, D.; Sengupta, M. R.; Chakraborty, A.; Maiti, B.; Biswas, A.; Sinha, D.

doi:10.1101/2025.09.25.678452

bioRxiv · 10.1101/2025.09.25.678452

SEASONAL PM2.5 DIFFERENTIALLY REGULATES JAK2/STAT3 SIGNALING IN RURAL AND URBAN COHORTS

Ghosh, S.·Chaudhuri, R.·Mukherjee, M.·Samanta, A.·Saha, P.·Henneman, L. R.·Majumdar, D.·Sengupta, M. R.·Chakraborty, A.·Maiti, B.·Biswas, A.·Sinha, D.

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Abstract

Ambient particulate matter (PM2.5) is a major environmental carcinogen linked to lung cancer, yet its molecular insights on asymptomatic non-smokers remains unclear. This study examined the effect of seasonal fluctuations of PM2.5 on oxidative stress and pro-oncogenic signaling in rural (RU) and urban (UR) cohorts from West Bengal, India. Environmental monitoring revealed higher PM2.5 and associated benzo[]pyrene in UR, during winter, induced oxidative stress (elevated ROS, 8-OHdG), reduced antioxidants (SOD, catalase, GPx), and promoted airway inflammation. Transcriptomic and bioinformatic analyses identified activation of IL-6/EGFR-driven JAK2/STAT3 signaling and its crosstalk with Ras/Raf/MAPK, leading to increased expression of downstream effectors (BCL-2, MCL-1, c-MYC, cyclin D1) and repression of tumor suppressors (BAX, p21). Notably, downregulation of JAK/STAT inhibitors PIAS2 and SOCS2 suggested persistent activation of oncogenic signaling. Linear mixed-effects models linked winter PM2.5 surges to oxidative stress, inflammation, and altered JAK2/STAT3 signaling, while regression models showed stronger responses in UR. Risk modeling predicted significantly higher lung cancer mortality in UR, underscoring the role of seasonal PM2.5 surges in JAK2/STAT3-driven carcinogenic susceptibility and the urgent need for targeted interventions.

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Ghosh, S., Chaudhuri, R., Mukherjee, M., Samanta, A., Saha, P., Henneman, L. R., Majumdar, D., Sengupta, M. R., Chakraborty, A., Maiti, B., Biswas, A., Sinha, D.. 2025-09-30. SEASONAL PM2.5 DIFFERENTIALLY REGULATES JAK2/STAT3 SIGNALING IN RURAL AND URBAN COHORTS. https://doi.org/10.1101/2025.09.25.678452

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