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One of the common memes I see about an ERE with Mesopotamia (or any state that isn't based in Iran/Mesopotamia) is that it is hard to effectively defend it.
Your challenge/point of discussion is just that.
I'm mainly curious as to what strategies could be used to make an invasion going East to West into Mesopotamia (or West to East into Iran) enough an issue that the Zagros Mountains could form a solid natural border in the same way the Alps or Rhine do in Europe.