A computational fluid dynamics (CFD) guided combustion system optimization was conducted for a heavy-duty compression-ignition engine with a gasoline-like fuel that has an anti-knock index (AKI) of 58. The primary goal was to design an optimized combustion system utilizing the high volatility and low sooting tendency of the fuel for improved fuel efficiency with minimal hardware modifications to the engine. The CFD model predictions were first validated against experimental results generated using the stock engine hardware. A comprehensive design of experiments (DoE) study was performed at different operating conditions on a world-leading supercomputer, MIRA at Argonne National Laboratory, to accelerate the development of an optimized fuel-efficiency focused design while maintaining the engine-out NOx and soot emissions levels of the baseline production engine. Compared to the base engine, the optimized results showed a significant improvement in closed-cycle, indicated specific fuel consumption (ISFC) across different engine speed and load points. When combined with modified injector configurations, the optimized piston bowl designs showed better in-cylinder air utilization and shorter combustion duration, thereby leading to improved fuel efficiency of up to 2.8%. In particular, increasing the injector hydraulic flow rate (larger nozzle diameter) was found to be beneficial by shortening the combustion duration while producing a higher incylinder combustion temperature for enhanced soot oxidation. A lower swirl ratio was also seen to be beneficial and the effects were attributed to the lower heat transfer loss and reduced need for fuel-air mixing. Increasing the compression ratio from 18.9 to 20.5 was also important for improving the fuel efficiency according to the relative contributions from key design parameters on ISFC.