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.

Early human evidence such as case series or small samples is exploring possible benefits.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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 ga

Evidence level

Early human evidence such as case series or small samples is exploring possible benefits.

Browse all related research

Filter the research library by this study's title keywords, author, or publication year.