As has already been said, the biggest thing you can to do an engine to reduce its fuel consumption is to replace it with a smaller one.
Another really major thing you can do is to not use it. Turn it off when you're sitting at a light, turn it off when you're coasting, and so forth.
Another thing is to operate it in its most efficient regime, typically right around 2000 RPM with a decent amount of load on the engine. Which means pulse and glide (or pulse and coast).
If you're talking about modifying an existing engine to get economy out of it, you can easily spend thousands or tens of thousands of dollars making changes that can get you a couple of percentage points of FE. Not worth it in any way, unless you're looking to set records. (In which case, the "smaller engine" idea is probably a better way to go.)
Since efficient driving is all at low RPMs, any changes you make that help the engine to work well at low RPMs have a chance of improving economy. Long tubular headers are one thing that comes to mind. A cam ground for torque at very low revs is another. A long-tube type intake might be as well. Increasing bearing clearances for low-friction operation. Friction reducing coatings on moving parts and on oil-shedding parts. Compression increases will help, possibly at the expense of requiring higher-octane fuel. Smaller valves to give good flow velocity at low RPMs. Lighter everything (including valve springs) so you spend less energy moving things around. And so on.
And all of that might net you, what, a 5% improvement if you're lucky?
Actually, one other area where engine mods can help fuel economy noticeably: If your engine has really major shortcomings or design flaws, correcting those can help. A friend with a 60s-vintage Mustang saw better economy when he replaced the awful stock exhaust manifold with real headers, for example.
Cars built in the last 30 years or so won't have easy gains like that available, though. When automakers had to start building for economy, they grabbed the low-hanging fruit first.
-soD
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