PBK-Loaded secretory autophagosomes drive radiotherapy-induced systemic adipose depletion via MAPK/ERK-PRKA/PKA-LIPE/HSL signaling: a therapeutic target for esophageal cancer cachexia

Radiotherapy, while a cornerstone treatment for esophageal squamous cell carcinoma (ESCC), is paradoxically associated with significant weight loss that portends poor patient outcomes. The mechanisms driving this metabolic complication remain elusive. Here, we identified adipose depletion – rather than muscle atrophy – as the primary contributor to radiotherapy-induced weight loss in ESCC. We demonstrated that secretory autophagosomes (SAPs) released post-irradiation mediate systemic fat loss through integrated in vitro and in vivo studies. Proteomic profiling revealed enrichment of PBK (PDZ binding kinase) in radiation-induced SAPs, with functional studies establishing PBK as the master regulator of adipocyte lipolysis. Mechanistically, SAP-delivered PBK activated MAPK1/ERK2 (mitogen-activated protein kinase 1), triggering a downstream PRKA/PKA-LIPE/HSL signaling cascade that increases lipolytic rate. Clinically, elevated circulating SAPs levels predicted severe fat loss and reduced median survival in a ESCC cohort. Critically, pharmacological inhibition of PBK with OTS-514 rescued adipose mass in preclinical models while enhancing tumor radiosensitivity. Our work redefines radiotherapy-induced cachexia as an adipose-centric process orchestrated by SAPs, unveils PBK as a therapeutic target, and provides actionable biomarkers for early intervention. These findings bridge the gap between localized radiotherapy and systemic metabolic sequelae, offering a dual-strategy approach to improve both survival and quality of life in ESCC patients. Abbreviations: ADSCs: adipose-derived stem cells; CM: conditioned media; ESCC: esophageal squamous cell carcinoma; EVs: extracellular vesicles; eWAT: epididymal white adipose tissue; GA: gastrocnemius muscle; iWAT: inguinal white adipose tissue; LIPE/HSL: lipase E, hormone sensitive type; LIR: LC3-interacting region; MAP2K1/MEK1: mitogen-activated protein kinase kinase 1; MAPK/ERK: mitogen-activated protein kinase; OS: overall survival; PBK: PDZ binding kinase; PRKA/PKA: protein kinase cAMP-dependent; RT: radiotherapy; SAPs: secretory autophagosomes; sEVs: small extracellular vesicles.