These days, if you're authoring from scratch, just write idiomatic TS in ESM, and you'll be fine. Even if targeting only Node, prefer to use Web standards (e.g., fetch, Request/Response, WebCrypto, Web Streams, URL, AbortController) as Node is migrating in that direction, and standard-compliant code will give you optionality in runtimes (Bun/Node/Workers).
I want to invest my time wisely and learn portable techniques, but I realize the scope of my ignorance may exceed what you can address in a comment forum!
Choose the tech stack that allows you to rapidly experiment in building something other people will give you money to use. That means choosing DX and iteration speed over runtime speed. That means using whatever gives you the most joy, so you're incentivized to build more often. That means something high-level so you don't waste time re-building components your customers don't care about, so you spend fewer hours on invisible, undifferentiated, but complex and time-consuming stuff.
If you're most effective with JS, Node is fine. Bun is fine. Deno is fine (for greenfield). One is super stable, battle-tested, and has 10x more contributors and 100x more libraries than the other two (most of them are trash). This maturity gap may not matter at all or may break your startup if you must re-implement something complex or continuously spend hours understanding and battling your runtime with minimal information on the web from others who encountered the same problem before. The same goes for your prod infrastructure, mobile app architecture, business ops, infosec, etc. Choose boring technology https://boringtechnology.club
I learned that problems that seem simple and solved apparently often aren't, regardless of how many blog posts and HN posts there are about the framework of the week. I needed to define an API, so I did so using OpenAPI. While the idea and standard seems mostly sound, the tooling (from editing to code generation) is absolute trash. I wasted soooo much time trying to make it work. Should I ever use it again, I'm writing my own tools. But right now I do just need to get stuff done.
I have never used Node and am creating a new project from scratch, so I don't know how worried to be about your commentary.