Authorities said the victim was driving northbound on the 5 Freeway near the Citadel Outlets when another driver pulled up next to him, drew a gun and fired once at the windshield.
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The victim pulled off the freeway and called for help at 1st Street and Boyle Avenue in Boyle Heights at about 8:30 p.m., according to California Highway Patrol.
The driver was able to communicate with first responders, but appeared badly bloodied.
He was in stable condition, according to the CHP.
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The victim's car, a red Ford, had one visible bullet hole in the windshield.
Officials initially said the motive appeared to be road rage, but a CHP spokesperson later declined the incident as such.
The suspect remained at large and the only description provided by officials was that the suspect was in a dark blue or black Chevrolet Suburban.