Extreme-scale earthquakes of (M8+) are catastrophic: intense ground shakings are generated by rapid energy release - equal to tens of nuclear explorations - in tens of seconds and sometimes followed by secondary hazards such as landslides and disaster tsunami waves. We still have limited knowledge of the energy buildup and release through nucleation, propagation and post-seismic relaxation of rapid earthquake rupture. Here we combine advanced numerical modelling techniques, experimental measurements, seismic and aseismic observations, to unravel the influence of transient stress and strength on megathurst earthquake nucleation and various fault weakening mechanisms in earthquake source physics. We firstly present two-step linked numerical simulations of long-term quasi-dynamic slow slip cycles model and dynamic rupture and seismic wave propagation across the same complex 3D megathrust geometry of the flat-slab segment in the Guerrero Seismic Gap, Mexico. We then present dynamic rupture models for the M8.2 Chignik megathrust earthquake considering 3D realistic slab geometry, high-resolution topo-bathymetry, variation of pore fluid pressure along with both dip- and strike-directions, and geodetically inferred fault coupling. Understanding the conditions governing the dynamics of megathrust earthquakes has the potential to advance our understanding of seismic hazards in subduction regions.