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Karst is the most common ore-controlling structure in Mississippi Valley-type (MVT) Pb–Zn deposits. However, the formation process of karst caves that contain ores and their related Pb–Zn mineralization in fold-thrust belts is poorly understood. The Changdong MVT Pb–Zn deposit is hosted by karst caves located in the fold-thrust system of the Simao basin, Sanjiang metallogenic belt, Tibetan Plateau. The Changdong deposit is an ideal natural laboratory for studying the effects of karst on Pb–Zn mineralization in MVT deposits. The ore bodies in this deposit are hosted by a large-scale carbonate breccia and bedded sediments belt within the late Permian limestones, which are situated in the hanging wall of the regional Longshu thrust fault. The δ13CV-PDB values of the limestone fragments from the breccias range from − 4.2 to 4.1‰. They are similar to those of overlying limestone strata, indicating that the fragments were mainly derived from autochthonous limestones in the overlying strata. Energy-dispersive spectroscopy analysis indicates that the bedded sediments and the matrices of the carbonate breccias contain K–Al silicate clay minerals, quartz, rock fragments, and calcite fragments. Detrital zircons from bedded sediments contain five discrete age populations ranging from the Jurassic to the Paleoproterozoic, indicating that the matrix materials were derived from the weathered sediments of metamorphic and magmatic rocks along the western margin of the Simao basin. Bedded sediments dominated by exogenous materials are actually speleothems. When contextualized with recently published data placing the Changdong deposit formation in the early to middle Oligocene, our data suggest that the Changdong deposit formed within a meteoric paleokarst system. The Pb–Zn ores are hosted by the speleothems in the breccia belt and comprise microspherulitic or colloidal sphalerite and euhedral galena. The sphalerite and galena precipitated by filling voids and replacing calcite crystals in faded speleothems. The pyrite and galena δ34SV-CDT values from the Changdong deposit range from − 16.9 to 15.8‰, indicating a pre-existing H2S reservoir interpreted as a result of bacterial sulfate reduction (BSR). A three-stage process for the Changdong deposit was proposed as last. First, the Permian limestone was uplifted to the near-surface by regional thrusting during the India-Eurasia collision, and karst caves formed by meteoric dissolution. Second, a reduced sulfur trap formed by BSR in the paleokarst caves during continual regional compression. Third, metal-rich fluids migrated into the Changdong deposit via tensile faults formed during the transition from compressive stress to extensional strike-slip stress as a result of progressive rotation of the regional strain axes. The Pb–Zn sulfides were likely precipitated by low-temperature fluid mixing. This study provides new data to establish a geologically consistent framework for the evaluation of karst caves and related MVT Pb–Zn mineralization in fold-thrust systems. [ABSTRACT FROM AUTHOR]