The hetero-aggregation of serpentine and sulfide minerals during flotation represents a persistent challenge in mineral engineering.A critical knowledge gap lies in the limited understanding of facet-specific interfacial interactions between sulfide minerals and different serpentine planes, preventing the effective modulation of interparticle hetero-aggregation behavior.This study quant. investigated the effect of three types of cyclohexane-based regulators (i.e., CYH-OH, CYH-COOH, and CYH-PO4) on the interparticle interactions between pyrite (FeS2, a typical sulfide mineral) and serpentine different planes at the nanoscale.Flotation separation results revealed that CYH-PO4 uniquely maintained >80 % pyrite recovery while effectively suppressing hetero-aggregation.Atomic force microscopy (AFM) force measurements unveiled a facet-dependent interaction behavior based on the electrostatic double layer (EDL) dominated, i.e., pyrite exhibited a strong attraction to serpentine MgOH plane but pure repulsion with SiO/MgSiO planes.Combined with the spectroscopic anal. and theor. simulation, such superior serpentine-pyrite separation performance of CYH-PO4 was attributed to its selective adsorption on MgOH plane via covalent bonding, which reversed the surface potential of MgOH plane, thereby tuning the interparticle interaction between pyrite and serpentine planes from strong attraction to repulsion.Notably, CYH-PO4 only had weak phys. adsorption on the pyrite surface, thus significantly enhancing the EDL repulsion between serpentine and pyrite.This work establishes a generalized framework for understanding the serpentine-pyrite hetero-aggregation behavior and mechanism, which can be further generalized to other mineral systems and provides valuable insights into developing the interparticle interaction modulation strategies at the nanoscale.